{"gene":"NIPA1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2006,"finding":"NIPA1 functions as a Mg2+ transporter: it mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.69 mM) when expressed in Xenopus oocytes. Endogenous NIPA1 localizes to early endosomes and the cell surface in neuronal and epithelial cells, and redistributes between these compartments in response to extracellular Mg2+ concentration. Disease-associated mutants T39R and G100R show loss-of-function in oocytes and altered trafficking in COS7 cells.","method":"Xenopus oocyte transport assay, immunofluorescence, transfected COS7 cell trafficking assay, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution in oocytes with functional assay, mutagenesis, and subcellular localization with functional consequence, multiple orthogonal methods in single rigorous study","pmids":["17166836"],"is_preprint":false},{"year":2009,"finding":"Mammalian NIPA1 physically interacts with the type II BMP receptor (BMPRII) — interaction does not require the BMPRII cytoplasmic tail — and inhibits BMP signalling by promoting endocytosis and lysosomal degradation of BMP receptors. Disease-associated NIPA1 mutants alter BMPRII trafficking and are less efficient at promoting BMPRII degradation than wild-type NIPA1.","method":"Co-immunoprecipitation, confocal microscopy, endocytosis/lysosomal degradation assay, disease mutant comparison","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional degradation assay plus trafficking experiments, replicated concept in Drosophila homologue and rat transgenic model (PMID:24128679)","pmids":["19620182"],"is_preprint":false},{"year":2008,"finding":"HSP-associated NIPA1 mutants (T45R and G106R) accumulate in the endoplasmic reticulum, trigger ER stress (unfolded protein response/UPR) and apoptotic cell death in cultured rat cortical neurons. In C. elegans, equivalent mutations in the NIPA1 homolog CeNIPA cause progressive neurodegeneration and paralysis via ER stress; neurodegeneration is suppressed in caspase (ced-3)- and UPR (xbp-1)-deficient backgrounds, establishing a gain-of-function ER stress mechanism.","method":"Neuronal transfection, flow cytometry (surface expression), C. elegans transgenic expression, genetic epistasis (ced-3 and xbp-1 mutant backgrounds), confocal microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in C. elegans plus cellular assays in mammalian neurons, multiple orthogonal methods establishing gain-of-function ER stress mechanism","pmids":["19091982"],"is_preprint":false},{"year":2010,"finding":"NIPA1 and atlastin-1 (SPG3A protein) are direct binding partners; their endogenous expression and trafficking are mutually dependent on co-expression. HSP-causing mutations in atlastin-1 (R239C, R495W) sequester the complex in the Golgi, while NIPA1 mutations (T45R, G106R) sequester it in the ER. Both sets of mutations reduce axonal and dendritic sprouting in cultured rat cortical neurons, placing NIPA1 and atlastin-1 in a common biochemical pathway supporting axonal maintenance.","method":"Co-immunoprecipitation, confocal microscopy, flow cytometry, neurite outgrowth assay in rat cortical neurons","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional neurite assay, single lab, multiple orthogonal methods","pmids":["20816793"],"is_preprint":false},{"year":2013,"finding":"In transgenic rats expressing human NIPA1 G106R mutation, BMPR2 protein expression is increased in spinal cord, consistent with impaired BMPR2 degradation. Histopathology reveals accumulation of tubulovesicular organelles with endosomal features at axonal and dendritic terminals, followed by multifocal vacuolar degeneration, establishing that the NIPA1 mutation disrupts endosomal trafficking in vivo.","method":"Transgenic rat model (Thy1.2-hNIPA1), immunohistochemistry, electron microscopy, behavioral and electrophysiological analysis","journal":"Journal of neuropathology and experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with morphological and biochemical readouts, single lab","pmids":["24128679"],"is_preprint":false},{"year":2018,"finding":"NIPA1 (SPG6) knockdown in AML cells (NB4 and MV4-11) results in decreased cell growth and elevated apoptosis, associated with increased BMPR2 expression, enhanced Smad1/5/9 phosphorylation, and decreased Bcl-2 and Bcl-xl transcription, indicating NIPA1 suppresses BMPR2-Smad signalling to promote AML cell survival.","method":"shRNA-lentiviral knockdown in human AML cell lines, western blot, cell growth and apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular and signalling phenotype, single lab, single study","pmids":["29715457"],"is_preprint":false},{"year":2025,"finding":"NIPA1 knockdown in M2 macrophages inhibits M2 macrophage polarization and AML cell survival via suppression of IGFBP2/EGFR signalling, and reduces anthracycline resistance in HL-60 and HL-60/ADR cells.","method":"shRNA knockdown in macrophages and AML co-culture, mouse xenograft model, signalling pathway analysis","journal":"Annals of hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, mechanism inferred from signalling readouts without biochemical reconstitution","pmids":["41085686"],"is_preprint":false},{"year":2023,"finding":"Functional studies showed that NIPA1 c.316G>A (p.G106R) mutation significantly reduces NIPA1 protein expression, whereas the c.316G>C mutation causing the same amino acid change does not affect protein expression; neither mutation affects splicing.","method":"Minigene splicing assay, RT-PCR, cell-based protein expression study","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (splicing and protein expression) in single study, single lab","pmids":["36607129"],"is_preprint":false}],"current_model":"NIPA1 is a multi-pass transmembrane Mg2+ transporter that localizes to early endosomes and the plasma membrane; it inhibits BMP signalling by physically interacting with BMPRII and promoting its endocytosis and lysosomal degradation, and forms a complex with atlastin-1 that is required for axonal maintenance — disease-causing mutations cause misfolding/ER retention that triggers UPR-mediated gain-of-function neurodegeneration and impair BMPRII degradation."},"narrative":{"mechanistic_narrative":"NIPA1 is a multi-pass transmembrane magnesium transporter that links endosomal trafficking to neuronal maintenance and is genetically tied to autosomal dominant hereditary spastic paraplegia. It mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.69 mM) and shuttles between early endosomes and the cell surface in response to extracellular Mg2+, with disease-associated mutants (T39R/T45R, G100R/G106R) showing loss of transport and altered trafficking [PMID:17166836]. NIPA1 physically interacts with the type II BMP receptor (BMPRII) independently of its cytoplasmic tail and suppresses BMP signalling by driving BMP receptor endocytosis and lysosomal degradation; disease mutants are deficient in promoting this degradation [PMID:19620182], and in vivo NIPA1 G106R rat spinal cord shows elevated BMPR2 alongside accumulation of endosomal tubulovesicular organelles and vacuolar degeneration [PMID:24128679]. NIPA1 forms a mutually dependent complex with atlastin-1 (SPG3A) that supports axonal and dendritic sprouting, with HSP mutations sequestering the complex in the ER (NIPA1 mutants) or Golgi (atlastin-1 mutants) [PMID:20816793]. Pathogenic HSP mutants accumulate in the ER, trigger an unfolded protein response, and cause neurodegeneration through a gain-of-function ER-stress mechanism dependent on caspase and UPR (xbp-1) activity [PMID:19091982]. Beyond its neuronal role, NIPA1 suppresses BMPR2–Smad signalling to promote acute myeloid leukemia cell survival [PMID:29715457].","teleology":[{"year":2006,"claim":"Established the molecular activity of NIPA1 by showing it is a bona fide Mg2+ transporter whose subcellular distribution responds to Mg2+, and that HSP mutations abolish this function — defining the wild-type role and a loss-of-function axis for disease.","evidence":"Xenopus oocyte transport assay, immunofluorescence and trafficking in COS7/neuronal cells, mutagenesis of T39R and G100R","pmids":["17166836"],"confidence":"High","gaps":["No structural model of the transport pore or transport stoichiometry","Physiological consequence of Mg2+-dependent redistribution not defined in neurons"]},{"year":2008,"claim":"Resolved the mechanism of mutant toxicity, showing HSP mutants are not simply loss-of-function but accumulate in the ER and kill neurons through UPR- and caspase-dependent gain-of-function ER stress.","evidence":"Neuronal transfection, surface-expression flow cytometry, and C. elegans transgenic genetic epistasis in ced-3 and xbp-1 backgrounds","pmids":["19091982"],"confidence":"High","gaps":["How ER retention is mechanistically coupled to misfolding not defined","Relative contribution of gain-of-function vs loss of Mg2+ transport in disease unresolved"]},{"year":2009,"claim":"Identified a signalling output for NIPA1 by showing it binds BMPRII and drives BMP receptor endocytic/lysosomal degradation, linking the transporter to BMP pathway suppression and giving disease mutants a second deficit.","evidence":"Reciprocal Co-immunoprecipitation, confocal microscopy, and lysosomal degradation assays with disease-mutant comparison","pmids":["19620182"],"confidence":"High","gaps":["Mechanism by which NIPA1 selects BMPRII for degradation unknown","Whether Mg2+ transport activity is required for receptor degradation untested"]},{"year":2010,"claim":"Placed NIPA1 in a defined biochemical pathway by demonstrating a direct, mutually dependent complex with atlastin-1 required for axonal/dendritic sprouting, unifying two HSP gene products in a common maintenance program.","evidence":"Reciprocal Co-IP, confocal microscopy, flow cytometry, and neurite outgrowth assays in rat cortical neurons","pmids":["20816793"],"confidence":"Medium","gaps":["Single-lab finding without independent confirmation","Functional purpose of the complex in mature axons in vivo not established"]},{"year":2013,"claim":"Validated the trafficking and BMPR2 defects in vivo, showing a NIPA1 G106R transgenic rat accumulates endosomal organelles and elevated BMPR2, connecting the cell-based mechanisms to a disease-relevant phenotype.","evidence":"Thy1.2-hNIPA1 G106R transgenic rat with immunohistochemistry, electron microscopy, behavioral and electrophysiological analysis","pmids":["24128679"],"confidence":"Medium","gaps":["Single model; causal chain from BMPR2 elevation to degeneration not dissected","Does not separate ER-stress and trafficking contributions"]},{"year":2018,"claim":"Extended NIPA1 function beyond neurons by showing it suppresses BMPR2–Smad signalling to promote AML cell survival, broadening its role to oncology.","evidence":"shRNA-lentiviral knockdown in NB4 and MV4-11 AML lines, western blot, growth and apoptosis assays","pmids":["29715457"],"confidence":"Medium","gaps":["Single study; mechanism inferred from signalling readouts","Whether Mg2+ transport contributes to the survival phenotype unknown"]},{"year":2023,"claim":"Clarified genotype-to-protein relationships by showing the c.316G>A G106R allele reduces NIPA1 protein while a synonymous-codon G106R variant does not, and neither alters splicing — refining how specific HSP mutations exert their effect.","evidence":"Minigene splicing assay, RT-PCR, and cell-based protein expression study","pmids":["36607129"],"confidence":"Medium","gaps":["Mechanism of allele-specific protein reduction not defined","Link between reduced protein level and neurodegenerative phenotype not tested"]},{"year":2025,"claim":"Implicated NIPA1 in the tumor microenvironment by showing its knockdown blocks M2 macrophage polarization and reduces AML survival and anthracycline resistance via IGFBP2/EGFR signalling.","evidence":"shRNA knockdown in macrophages with AML co-culture, mouse xenograft, signalling analysis","pmids":["41085686"],"confidence":"Low","gaps":["Single low-confidence study; mechanism inferred without biochemical reconstitution","Direct interaction of NIPA1 with IGFBP2/EGFR pathway not shown","Relationship to the BMPR2–Smad axis unclear"]},{"year":null,"claim":"How NIPA1's Mg2+ transport activity, BMPRII degradation function, and atlastin-1 complex are mechanistically coordinated — and which is most relevant to neurodegeneration versus its oncogenic roles — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of NIPA1 or its complexes","No reconstitution coupling transport activity to receptor degradation","Relative weight of loss-of-function vs gain-of-function in disease unsettled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2]}],"complexes":[],"partners":["BMPR2","ATL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7RTP0","full_name":"Magnesium transporter NIPA1","aliases":["Non-imprinted in Prader-Willi/Angelman syndrome region protein 1","Spastic paraplegia 6 protein"],"length_aa":329,"mass_kda":34.6,"function":"Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Fe(2+), Sr(2+), Ba(2+), Zn(2+) and Co(2+) but to a much less extent than Mg(2+) (By similarity)","subcellular_location":"Cell membrane; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q7RTP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NIPA1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NIPA1","total_profiled":1310},"omim":[{"mim_id":"615656","title":"CHROMOSOME 15q11.2 DELETION SYNDROME","url":"https://www.omim.org/entry/615656"},{"mim_id":"608147","title":"TUBULIN-GAMMA COMPLEX-ASSOCIATED PROTEIN 5; TUBGCP5","url":"https://www.omim.org/entry/608147"},{"mim_id":"608146","title":"NIPA MAGNESIUM TRANSPORTER 2; NIPA2","url":"https://www.omim.org/entry/608146"},{"mim_id":"608145","title":"NIPA MAGNESIUM TRANSPORTER 1; NIPA1","url":"https://www.omim.org/entry/608145"},{"mim_id":"606322","title":"CYTOPLASMIC FMRP-INTERACTING PROTEIN 1; CYFIP1","url":"https://www.omim.org/entry/606322"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":56.5}],"url":"https://www.proteinatlas.org/search/NIPA1"},"hgnc":{"alias_symbol":["MGC35570","SLC57A1"],"prev_symbol":["SPG6"]},"alphafold":{"accession":"Q7RTP0","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTP0-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NIPA1","jax_strain_url":"https://www.jax.org/strain/search?query=NIPA1"},"sequence":{"accession":"Q7RTP0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7RTP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7RTP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTP0"}},"corpus_meta":[{"pmid":"14508710","id":"PMC_14508710","title":"NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6).","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14508710","citation_count":152,"is_preprint":false},{"pmid":"17166836","id":"PMC_17166836","title":"NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17166836","citation_count":118,"is_preprint":false},{"pmid":"19620182","id":"PMC_19620182","title":"The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19620182","citation_count":107,"is_preprint":false},{"pmid":"15711826","id":"PMC_15711826","title":"A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.","date":"2005","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15711826","citation_count":45,"is_preprint":false},{"pmid":"22378146","id":"PMC_22378146","title":"NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22378146","citation_count":45,"is_preprint":false},{"pmid":"15643603","id":"PMC_15643603","title":"Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.","date":"2005","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15643603","citation_count":45,"is_preprint":false},{"pmid":"19091982","id":"PMC_19091982","title":"Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19091982","citation_count":36,"is_preprint":false},{"pmid":"21599812","id":"PMC_21599812","title":"NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy.","date":"2011","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21599812","citation_count":26,"is_preprint":false},{"pmid":"20816793","id":"PMC_20816793","title":"The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1.","date":"2010","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/20816793","citation_count":24,"is_preprint":false},{"pmid":"22302102","id":"PMC_22302102","title":"TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation.","date":"2012","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/22302102","citation_count":24,"is_preprint":false},{"pmid":"16267846","id":"PMC_16267846","title":"Clinical and genetic study of a Brazilian family with spastic paraplegia (SPG6 locus).","date":"2006","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/16267846","citation_count":19,"is_preprint":false},{"pmid":"16795073","id":"PMC_16795073","title":"Novel SPG6 mutation p.A100T in a Japanese family with autosomal dominant form of hereditary spastic paraplegia.","date":"2006","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/16795073","citation_count":18,"is_preprint":false},{"pmid":"21419568","id":"PMC_21419568","title":"Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1.","date":"2011","source":"Clinical neurology and neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/21419568","citation_count":15,"is_preprint":false},{"pmid":"18191948","id":"PMC_18191948","title":"Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.","date":"2008","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18191948","citation_count":14,"is_preprint":false},{"pmid":"36736696","id":"PMC_36736696","title":"LncRNA NIPA1-SO confers atherosclerotic protection by suppressing the transmembrane protein NIPA1.","date":"2023","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/36736696","citation_count":13,"is_preprint":false},{"pmid":"34863451","id":"PMC_34863451","title":"SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review.","date":"2021","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/34863451","citation_count":12,"is_preprint":false},{"pmid":"17928003","id":"PMC_17928003","title":"Clinical and genetic study of SPG6 mutation in a Chinese family with hereditary spastic paraplegia.","date":"2007","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17928003","citation_count":12,"is_preprint":false},{"pmid":"24128679","id":"PMC_24128679","title":"Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.","date":"2013","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24128679","citation_count":12,"is_preprint":false},{"pmid":"30342661","id":"PMC_30342661","title":"Prenatal diagnosis of a familial 15q11.2 (BP1-BP2) microdeletion encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 in a fetus with ventriculomegaly, microcephaly and intrauterine growth restriction on prenatal ultrasound.","date":"2018","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/30342661","citation_count":12,"is_preprint":false},{"pmid":"34179866","id":"PMC_34179866","title":"Repeats expansions in ATXN2, NOP56, NIPA1 and ATXN1 are not associated with ALS in Africans.","date":"2021","source":"IBRO neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/34179866","citation_count":10,"is_preprint":false},{"pmid":"32500351","id":"PMC_32500351","title":"Is NIPA1-associated hereditary spastic paraplegia always 'pure'? Further evidence of motor neurone disease and epilepsy as rare manifestations.","date":"2020","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32500351","citation_count":9,"is_preprint":false},{"pmid":"31286297","id":"PMC_31286297","title":"Analysis of the GCG repeat length in NIPA1 gene in C9orf72-mediated ALS in a large Italian ALS cohort.","date":"2019","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/31286297","citation_count":8,"is_preprint":false},{"pmid":"36607129","id":"PMC_36607129","title":"Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia.","date":"2023","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36607129","citation_count":5,"is_preprint":false},{"pmid":"29715457","id":"PMC_29715457","title":"SPG6 supports development of acute myeloid leukemia by regulating BMPR2-Smad-Bcl-2/Bcl-xl signaling.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29715457","citation_count":5,"is_preprint":false},{"pmid":"24075313","id":"PMC_24075313","title":"Recurrent de novo c.316G>A mutation in NIPA1 hotspot.","date":"2013","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24075313","citation_count":5,"is_preprint":false},{"pmid":"35464835","id":"PMC_35464835","title":"Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35464835","citation_count":4,"is_preprint":false},{"pmid":"34108639","id":"PMC_34108639","title":"A novel de novo NIPA1 missense mutation associated to hereditary spastic paraplegia.","date":"2021","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34108639","citation_count":3,"is_preprint":false},{"pmid":"38667292","id":"PMC_38667292","title":"Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38667292","citation_count":0,"is_preprint":false},{"pmid":"41085686","id":"PMC_41085686","title":"NIPA1 depletion in tumor-associated macrophages via IGFBP2/EGFR attenuates acute myeloid leukemia progression and chemoresistance.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41085686","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14803,"output_tokens":2183,"usd":0.038577,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9194,"output_tokens":3150,"usd":0.06236,"stage2_stop_reason":"end_turn"},"total_usd":0.100937,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"NIPA1 functions as a Mg2+ transporter: it mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.69 mM) when expressed in Xenopus oocytes. Endogenous NIPA1 localizes to early endosomes and the cell surface in neuronal and epithelial cells, and redistributes between these compartments in response to extracellular Mg2+ concentration. Disease-associated mutants T39R and G100R show loss-of-function in oocytes and altered trafficking in COS7 cells.\",\n      \"method\": \"Xenopus oocyte transport assay, immunofluorescence, transfected COS7 cell trafficking assay, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution in oocytes with functional assay, mutagenesis, and subcellular localization with functional consequence, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"17166836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian NIPA1 physically interacts with the type II BMP receptor (BMPRII) — interaction does not require the BMPRII cytoplasmic tail — and inhibits BMP signalling by promoting endocytosis and lysosomal degradation of BMP receptors. Disease-associated NIPA1 mutants alter BMPRII trafficking and are less efficient at promoting BMPRII degradation than wild-type NIPA1.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, endocytosis/lysosomal degradation assay, disease mutant comparison\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional degradation assay plus trafficking experiments, replicated concept in Drosophila homologue and rat transgenic model (PMID:24128679)\",\n      \"pmids\": [\"19620182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HSP-associated NIPA1 mutants (T45R and G106R) accumulate in the endoplasmic reticulum, trigger ER stress (unfolded protein response/UPR) and apoptotic cell death in cultured rat cortical neurons. In C. elegans, equivalent mutations in the NIPA1 homolog CeNIPA cause progressive neurodegeneration and paralysis via ER stress; neurodegeneration is suppressed in caspase (ced-3)- and UPR (xbp-1)-deficient backgrounds, establishing a gain-of-function ER stress mechanism.\",\n      \"method\": \"Neuronal transfection, flow cytometry (surface expression), C. elegans transgenic expression, genetic epistasis (ced-3 and xbp-1 mutant backgrounds), confocal microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in C. elegans plus cellular assays in mammalian neurons, multiple orthogonal methods establishing gain-of-function ER stress mechanism\",\n      \"pmids\": [\"19091982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NIPA1 and atlastin-1 (SPG3A protein) are direct binding partners; their endogenous expression and trafficking are mutually dependent on co-expression. HSP-causing mutations in atlastin-1 (R239C, R495W) sequester the complex in the Golgi, while NIPA1 mutations (T45R, G106R) sequester it in the ER. Both sets of mutations reduce axonal and dendritic sprouting in cultured rat cortical neurons, placing NIPA1 and atlastin-1 in a common biochemical pathway supporting axonal maintenance.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, flow cytometry, neurite outgrowth assay in rat cortical neurons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional neurite assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20816793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In transgenic rats expressing human NIPA1 G106R mutation, BMPR2 protein expression is increased in spinal cord, consistent with impaired BMPR2 degradation. Histopathology reveals accumulation of tubulovesicular organelles with endosomal features at axonal and dendritic terminals, followed by multifocal vacuolar degeneration, establishing that the NIPA1 mutation disrupts endosomal trafficking in vivo.\",\n      \"method\": \"Transgenic rat model (Thy1.2-hNIPA1), immunohistochemistry, electron microscopy, behavioral and electrophysiological analysis\",\n      \"journal\": \"Journal of neuropathology and experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with morphological and biochemical readouts, single lab\",\n      \"pmids\": [\"24128679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NIPA1 (SPG6) knockdown in AML cells (NB4 and MV4-11) results in decreased cell growth and elevated apoptosis, associated with increased BMPR2 expression, enhanced Smad1/5/9 phosphorylation, and decreased Bcl-2 and Bcl-xl transcription, indicating NIPA1 suppresses BMPR2-Smad signalling to promote AML cell survival.\",\n      \"method\": \"shRNA-lentiviral knockdown in human AML cell lines, western blot, cell growth and apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular and signalling phenotype, single lab, single study\",\n      \"pmids\": [\"29715457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NIPA1 knockdown in M2 macrophages inhibits M2 macrophage polarization and AML cell survival via suppression of IGFBP2/EGFR signalling, and reduces anthracycline resistance in HL-60 and HL-60/ADR cells.\",\n      \"method\": \"shRNA knockdown in macrophages and AML co-culture, mouse xenograft model, signalling pathway analysis\",\n      \"journal\": \"Annals of hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, mechanism inferred from signalling readouts without biochemical reconstitution\",\n      \"pmids\": [\"41085686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Functional studies showed that NIPA1 c.316G>A (p.G106R) mutation significantly reduces NIPA1 protein expression, whereas the c.316G>C mutation causing the same amino acid change does not affect protein expression; neither mutation affects splicing.\",\n      \"method\": \"Minigene splicing assay, RT-PCR, cell-based protein expression study\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (splicing and protein expression) in single study, single lab\",\n      \"pmids\": [\"36607129\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NIPA1 is a multi-pass transmembrane Mg2+ transporter that localizes to early endosomes and the plasma membrane; it inhibits BMP signalling by physically interacting with BMPRII and promoting its endocytosis and lysosomal degradation, and forms a complex with atlastin-1 that is required for axonal maintenance — disease-causing mutations cause misfolding/ER retention that triggers UPR-mediated gain-of-function neurodegeneration and impair BMPRII degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NIPA1 is a multi-pass transmembrane magnesium transporter that links endosomal trafficking to neuronal maintenance and is genetically tied to autosomal dominant hereditary spastic paraplegia. It mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.69 mM) and shuttles between early endosomes and the cell surface in response to extracellular Mg2+, with disease-associated mutants (T39R/T45R, G100R/G106R) showing loss of transport and altered trafficking [#0]. NIPA1 physically interacts with the type II BMP receptor (BMPRII) independently of its cytoplasmic tail and suppresses BMP signalling by driving BMP receptor endocytosis and lysosomal degradation; disease mutants are deficient in promoting this degradation [#1], and in vivo NIPA1 G106R rat spinal cord shows elevated BMPR2 alongside accumulation of endosomal tubulovesicular organelles and vacuolar degeneration [#4]. NIPA1 forms a mutually dependent complex with atlastin-1 (SPG3A) that supports axonal and dendritic sprouting, with HSP mutations sequestering the complex in the ER (NIPA1 mutants) or Golgi (atlastin-1 mutants) [#3]. Pathogenic HSP mutants accumulate in the ER, trigger an unfolded protein response, and cause neurodegeneration through a gain-of-function ER-stress mechanism dependent on caspase and UPR (xbp-1) activity [#2]. Beyond its neuronal role, NIPA1 suppresses BMPR2–Smad signalling to promote acute myeloid leukemia cell survival [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the molecular activity of NIPA1 by showing it is a bona fide Mg2+ transporter whose subcellular distribution responds to Mg2+, and that HSP mutations abolish this function — defining the wild-type role and a loss-of-function axis for disease.\",\n      \"evidence\": \"Xenopus oocyte transport assay, immunofluorescence and trafficking in COS7/neuronal cells, mutagenesis of T39R and G100R\",\n      \"pmids\": [\"17166836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the transport pore or transport stoichiometry\", \"Physiological consequence of Mg2+-dependent redistribution not defined in neurons\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the mechanism of mutant toxicity, showing HSP mutants are not simply loss-of-function but accumulate in the ER and kill neurons through UPR- and caspase-dependent gain-of-function ER stress.\",\n      \"evidence\": \"Neuronal transfection, surface-expression flow cytometry, and C. elegans transgenic genetic epistasis in ced-3 and xbp-1 backgrounds\",\n      \"pmids\": [\"19091982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ER retention is mechanistically coupled to misfolding not defined\", \"Relative contribution of gain-of-function vs loss of Mg2+ transport in disease unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a signalling output for NIPA1 by showing it binds BMPRII and drives BMP receptor endocytic/lysosomal degradation, linking the transporter to BMP pathway suppression and giving disease mutants a second deficit.\",\n      \"evidence\": \"Reciprocal Co-immunoprecipitation, confocal microscopy, and lysosomal degradation assays with disease-mutant comparison\",\n      \"pmids\": [\"19620182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NIPA1 selects BMPRII for degradation unknown\", \"Whether Mg2+ transport activity is required for receptor degradation untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed NIPA1 in a defined biochemical pathway by demonstrating a direct, mutually dependent complex with atlastin-1 required for axonal/dendritic sprouting, unifying two HSP gene products in a common maintenance program.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal microscopy, flow cytometry, and neurite outgrowth assays in rat cortical neurons\",\n      \"pmids\": [\"20816793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent confirmation\", \"Functional purpose of the complex in mature axons in vivo not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Validated the trafficking and BMPR2 defects in vivo, showing a NIPA1 G106R transgenic rat accumulates endosomal organelles and elevated BMPR2, connecting the cell-based mechanisms to a disease-relevant phenotype.\",\n      \"evidence\": \"Thy1.2-hNIPA1 G106R transgenic rat with immunohistochemistry, electron microscopy, behavioral and electrophysiological analysis\",\n      \"pmids\": [\"24128679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single model; causal chain from BMPR2 elevation to degeneration not dissected\", \"Does not separate ER-stress and trafficking contributions\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended NIPA1 function beyond neurons by showing it suppresses BMPR2–Smad signalling to promote AML cell survival, broadening its role to oncology.\",\n      \"evidence\": \"shRNA-lentiviral knockdown in NB4 and MV4-11 AML lines, western blot, growth and apoptosis assays\",\n      \"pmids\": [\"29715457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; mechanism inferred from signalling readouts\", \"Whether Mg2+ transport contributes to the survival phenotype unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified genotype-to-protein relationships by showing the c.316G>A G106R allele reduces NIPA1 protein while a synonymous-codon G106R variant does not, and neither alters splicing — refining how specific HSP mutations exert their effect.\",\n      \"evidence\": \"Minigene splicing assay, RT-PCR, and cell-based protein expression study\",\n      \"pmids\": [\"36607129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of allele-specific protein reduction not defined\", \"Link between reduced protein level and neurodegenerative phenotype not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated NIPA1 in the tumor microenvironment by showing its knockdown blocks M2 macrophage polarization and reduces AML survival and anthracycline resistance via IGFBP2/EGFR signalling.\",\n      \"evidence\": \"shRNA knockdown in macrophages with AML co-culture, mouse xenograft, signalling analysis\",\n      \"pmids\": [\"41085686\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single low-confidence study; mechanism inferred without biochemical reconstitution\", \"Direct interaction of NIPA1 with IGFBP2/EGFR pathway not shown\", \"Relationship to the BMPR2–Smad axis unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NIPA1's Mg2+ transport activity, BMPRII degradation function, and atlastin-1 complex are mechanistically coordinated — and which is most relevant to neurodegeneration versus its oncogenic roles — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of NIPA1 or its complexes\", \"No reconstitution coupling transport activity to receptor degradation\", \"Relative weight of loss-of-function vs gain-of-function in disease unsettled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BMPR2\", \"ATL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":5,"faith_pct":60.0}}