Affinage

SAMD12

Sterile alpha motif domain-containing protein 12 · UniProt Q8N8I0

Length
201 aa
Mass
22.9 kDa
Annotated
2026-04-28
17 papers in source corpus 6 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SAMD12 is a sterile alpha motif domain-containing protein that functions as a negative regulator of MAP4K kinase signaling at neuronal synapses. SAMD12 binds CNKSR1/2/3 scaffold proteins with high affinity and competitively displaces MAP4K kinases (MAP4K4, MINK1, TNIK) from these scaffolds, thereby inhibiting TNIK activity and modulating synapse development (PMID:40010432). Intronic TTTCA and TTTTA pentanucleotide repeat expansions in SAMD12 cause familial cortical myoclonic tremor with epilepsy (BAFME1/FCMTE1), with the expanded repeat alleles exhibiting intergenerational instability (PMID:30194086, PMID:33681653).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2018 High

    The genetic basis of BAFME1/FCMTE1 was resolved: intronic pentanucleotide repeat expansions in SAMD12 were identified as the causative mutations, establishing this gene as the disease locus after years of linkage studies had narrowed the interval.

    Evidence Long-read sequencing (PacBio/Nanopore), repeat-primed PCR, and co-segregation analysis across multiple affected pedigrees in Chinese and Japanese cohorts

    PMID:29939203 PMID:30194086 PMID:30559482

    Open questions at the time
    • Whether pathogenesis is driven by RNA toxicity from repeat transcripts, loss of SAMD12 protein function, or both remains unresolved
    • No mechanism linking the repeat expansion to cortical myoclonus or epileptogenesis was established
  2. 2021 Medium

    The SAMD12 repeat expansion was shown to be meiotically unstable, undergoing both contraction and expansion across generations, providing a molecular basis for variable clinical severity and anticipation observed in BAFME1 families.

    Evidence PacBio sequencing of long-range PCR products across parent-offspring transmissions

    PMID:33681653

    Open questions at the time
    • The relationship between repeat length and disease severity or age of onset was not quantitatively defined
    • Somatic mosaicism of repeat length in brain tissue has not been characterized
  3. 2025 Medium

    The first protein-level function of SAMD12 was established: it acts as a competitive inhibitor of MAP4K kinase–scaffold interactions by binding CNKSR1/2/3 with high affinity and displacing TNIK/MINK1/MAP4K4, with functional consequences for neuronal synapse development.

    Evidence Binding affinity measurements, competitive displacement assays, and ectopic expression with synapse development readouts in a single-lab study

    PMID:40010432

    Open questions at the time
    • Independent replication of the SAMD12–CNKSR competitive displacement mechanism has not been reported
    • Whether SAMD12 loss-of-function (as might occur from repeat expansion) dysregulates TNIK signaling in patient neurons is untested
    • Structural basis of the high-affinity SAMD12–CNKSR interaction is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A critical open question is whether the BAFME1-associated repeat expansion causes disease through loss of SAMD12 protein function (and consequent derepression of MAP4K/TNIK signaling), RNA gain-of-function toxicity, or a combination of both mechanisms.
  • No animal model recapitulating both the repeat expansion and BAFME1 phenotype has been reported
  • SAMD12 protein levels and TNIK activity have not been measured in patient-derived neurons
  • The endogenous expression pattern of SAMD12 in human brain regions relevant to BAFME1 is poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2
Partners
CNKSR1CNKSR2CNKSR3MAP4K4MINK1TNIK

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Intronic TTTCA and TTTTA pentanucleotide repeat expansions in intron 4 of SAMD12 are the causative mutations for familial cortical myoclonic tremor with epilepsy (FCMTE/BAFME1), identified by long-read sequencing and validated by repeat-primed PCR with co-segregation in affected pedigrees. Long-read sequencing (PacBio/Oxford Nanopore), repeat-primed PCR, long-range PCR, co-segregation analysis Journal of medical genetics High 29939203 30194086 30559482
2025 SAMD12 protein binds to CNKSR1/2/3 scaffold proteins with exceptionally strong affinity and competitively displaces MAP4K kinases (MAP4K4, MINK1, TNIK) from CNKSR1/2/3 scaffolds, thereby decoupling these kinases from their scaffold and inhibiting TNIK activity; ectopic expression of SAMD12 alters neuronal synapse development through this mechanism. Protein interaction characterization (binding affinity measurements), competitive displacement assays, ectopic expression with synapse development readout Journal of molecular biology Medium 40010432
2025 CNKSR2 acts as both a scaffold and an activator of TNIK during neuronal synapse development, and SAMD12 can inhibit TNIK activity by dissociating TNIK from the CNKSR2 complex. Biochemical interaction assays, ectopic expression, synapse development functional assays Journal of molecular biology Medium 40010432
2023 miR-106a-5p derived from liver fibrosis exosomes targets SAMD12, and knockdown of SAMD12 in liver cancer cell lines exacerbates cell proliferation, indicating SAMD12 suppresses hepatocellular carcinoma cell growth. In vitro knockdown with proliferation assay, in vivo validation PloS one Low 37228062
2021 The SAMD12 TTTCA/TTTTA repeat expansion mutant allele is unstable and can undergo both contraction and expansion upon intergenerational transmission, with allele sizes varying in repeat copy number between generations. PacBio sequencing of long-range PCR products, repeat-primed PCR Epilepsia open Medium 33681653

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy. Journal of medical genetics 80 30194086
2018 Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. Brain : a journal of neurology 76 29939203
2018 Detecting a long insertion variant in SAMD12 by SMRT sequencing: implications of long-read whole-genome sequencing for repeat expansion diseases. Journal of human genetics 38 30559482
2019 LncRNA SAMD12-AS1 promotes cell proliferation and inhibits apoptosis by interacting with NPM1. Scientific reports 27 31406141
2020 Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families. European journal of human genetics : EJHG 25 32203200
2021 LncRNA SAMD12-AS1 Promotes the Progression of Gastric Cancer via DNMT1/p53 Axis. Archives of medical research 22 33962804
2020 Founder effect of the TTTCA repeat insertions in SAMD12 causing BAFME1. European journal of human genetics : EJHG 16 32973343
2019 RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas. Molecular genetics & genomic medicine 15 30632316
2019 LncRNA SAMD12-AS1 down-regulates P53 to promote malignant progression of glioma. European review for medical and pharmacological sciences 14 31646576
2021 Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and SAMD12 intronic repeat expansion. Epilepsia open 13 33681653
2020 DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A. Journal of human genetics 13 33040085
2020 TTTCA Repeat Expansion of SAMD12 in a New Benign Adult Familial Myoclonic Epilepsy Pedigree. Frontiers in neurology 9 32174879
2020 Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in the SAMD12 gene. Brain communications 9 33501421
2023 Liver fibrosis-derived exosomal miR-106a-5p facilitates the malignancy by targeting SAMD12 and CADM2 in hepatocellular carcinoma. PloS one 6 37228062
2022 LncRNA SAMD12-AS1 Suppresses Proliferation and Migration of Hepatocellular Carcinoma via p53 Signaling Pathway. Journal of oncology 3 36052283
2025 SAMD12 as a Master Regulator of MAP4Ks by Decoupling Kinases From the CNKSR2 Scaffold. Journal of molecular biology 0 40010432
2023 Generation of an induced pluripotent stem cell line (ZJUi013-A) from a Familial cortical myoclonic tremor with epilepsy type 1 patient carrying (TTTCA)n insertion in the SAMD12 gene. Stem cell research 0 37890330