Affinage

QRICH2

Glutamine-rich protein 2 · UniProt Q9H0J4

Length
1663 aa
Mass
180.8 kDa
Annotated
2026-06-10
19 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

QRICH2 is a testis-restricted cytoskeletal protein essential for sperm flagellar biogenesis, whose loss causes multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility across humans, mice, and cattle (PMID:30683861, PMID:31292949, PMID:35255804). Mechanistically, QRICH2 stabilizes and sustains the expression of flagellar development proteins (PMID:30683861) and physically interacts with AKAP4 at the fibrous sheath, an interaction required for fibrous sheath formation and for maintaining QRICH2 protein levels in spermatozoa (PMID:34415320). QRICH2 functions as a glutamine sensor that couples Gln/Glu metabolism to tubulin glutamylation and microtubule stability in the flagellum, with its loss producing dysregulated Gln/Glu balance, mitochondrial protein mislocalization, and impaired motility — a phenotype reproduced by dietary Gln/Glu deprivation (PMID:38597976). Its N-terminal region carries antioxidant activity that protects spermatids from ROS-induced DNA damage, autophagy, and apoptosis (PMID:38772286). QRICH2 acts downstream of CFAP70 in the flagellar assembly pathway (PMID:37352829) and localizes to distinct compartments across spermatogenesis, residing in both the head and flagellum of mature sperm (PMID:41575150).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2019 High

    Established QRICH2 as a gene required for sperm flagellar formation and defined its molecular role as a stabilizer of flagellar development proteins, linking it directly to human MMAF and infertility.

    Evidence CRISPR-Cas9 knockout mice with MMAF phenotype plus proteomic analysis of testes and human variant identification

    PMID:30683861 PMID:31292949

    Open questions at the time
    • Which specific flagellar proteins QRICH2 stabilizes was not resolved at the molecular level
    • Heterozygous variants alone are not pathogenic, leaving the threshold of QRICH2 dose unclear
  2. 2021 Medium

    Identified a direct physical partner, showing QRICH2 interacts with AKAP4 at the fibrous sheath and that this interaction maintains QRICH2 expression — connecting QRICH2 to a defined flagellar structural assembly.

    Evidence Reciprocal Co-IP and immunofluorescence co-localization in HEK-293T cells plus expression analysis in AKAP4-variant patient sperm

    PMID:34415320

    Open questions at the time
    • Interaction interface and stoichiometry not mapped
    • Whether the dependency is mutual or unidirectional not fully resolved
  3. 2022 Medium

    Demonstrated cross-species conservation of QRICH2 function by showing a frameshift variant causes MMAF in cattle via nonsense-mediated decay of the transcript.

    Evidence Genome sequencing of affected bulls, testis transcriptome NMD analysis, and semen phenotyping

    PMID:35255804

    Open questions at the time
    • Does not add mechanistic detail beyond confirming loss-of-function phenotype
  4. 2023 Medium

    Placed QRICH2 within a genetic hierarchy by showing CFAP70 acts upstream, controlling QRICH2 expression during flagellar assembly.

    Evidence Cfap70 knockout mouse model with QRICH2 protein expression analysis

    PMID:37352829

    Open questions at the time
    • Whether CFAP70 regulates QRICH2 transcriptionally or post-translationally is unknown
    • Direct versus indirect regulation not distinguished
  5. 2024 Medium

    Defined a metabolic-sensing mechanism: QRICH2 acts as a glutamine sensor linking Gln/Glu metabolism to tubulin glutamylation, microtubule stability, and mitochondrial positioning in the flagellum.

    Evidence Qrich2 KO mouse with metabolic profiling, tubulin glutamylation assays, mitochondrial localization, and dietary Gln/Glu deprivation phenocopy

    PMID:38597976

    Open questions at the time
    • Molecular basis of Gln sensing by QRICH2 not structurally defined
    • Direct enzymatic role in glutamylation versus regulatory role not separated
  6. 2024 Medium

    Assigned a cytoprotective function: the QRICH2 N-terminus has intrinsic antioxidant activity protecting spermatids from ROS-induced damage.

    Evidence Qrich2 KO mouse phenotyping for ROS, DNA damage, autophagy and apoptosis plus in vitro incubation with purified N-terminal QRICH2 protein

    PMID:38772286

    Open questions at the time
    • Biochemical mechanism of antioxidant activity not characterized
    • Relationship between antioxidant and cytoskeletal functions not integrated
  7. 2026 Medium

    Characterized QRICH2 as a paralog-free, mammal-conserved, testis-restricted protein with two functional domains that relocalizes across spermatogenesis and acts as a cytoskeletal component in both sperm head and flagellum.

    Evidence Mass spectrometry isoform identification, in silico conservation analysis, immunodetection across 12 human organs, and proteomic dataset analysis

    PMID:41575150

    Open questions at the time
    • Functional contribution of QRICH2 in the sperm head not defined
    • Domain-specific activities not mapped to localization changes

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the metabolic-sensing, antioxidant, and structural functions of QRICH2 are mechanistically integrated, and the molecular basis of its glutamine sensing, remain unresolved.
  • No structural model of QRICH2 domains
  • No defined enzymatic mechanism for glutamine sensing or antioxidant activity
  • Direct flagellar protein clients not catalogued

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0005198 structural molecule activity 1 GO:0016209 antioxidant activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005929 cilium 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1474165 Reproduction 2
Partners
AKAP4CFAP70
Complex memberships
fibrous sheath

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 QRICH2 is required for sperm flagellar formation; loss-of-function mutations cause MMAF in humans and Qrich2 knockout male mice show MMAF phenotype and sterility. Proteomic analysis of KO vs wild-type testes revealed that QRICH2 stabilizes and enhances expression of proteins related to flagellar development. CRISPR-Cas9 knockout mice, proteomic analysis of testes, in vitro experiments Nature communications High 30683861
2019 Homozygous loss-of-function variants in QRICH2 (nonsense mutations c.3501C>G and c.4614C>G) confirmed as causative for MMAF syndrome; heterozygous QRICH2 variants were found at comparable rates in MMAF patients and controls, indicating heterozygous variants alone are not pathogenic for MMAF. Whole exome sequencing of 167 MMAF-affected subjects, variant analysis Clinical genetics Medium 31292949
2021 QRICH2 physically interacts with AKAP4 (A-kinase anchor protein 4) in sperm; co-localization and co-immunoprecipitation demonstrated their interaction, and a hemizygous loss-of-function AKAP4 variant reduces QRICH2 protein expression in spermatozoa, indicating AKAP4 is required for maintaining QRICH2 expression and that their interaction is necessary for fibrous sheath formation. Immunofluorescence co-localization, co-immunoprecipitation (Co-IP) in HEK-293T cells, protein expression analysis in patient spermatozoa Human molecular genetics Medium 34415320
2022 A 1-bp deletion causing a frameshift and premature termination codon in bovine QRICH2 leads to low sperm count and immotile sperm with multiple morphological abnormalities of the flagellum; the mutant transcript undergoes nonsense-mediated mRNA decay as shown by testis transcriptome analysis. Genome sequencing of affected bull, testis transcriptome analysis (nonsense-mediated decay), semen analysis Genetics, selection, evolution : GSE Medium 35255804
2024 QRICH2 acts as a glutamine (Gln) sensor in sperm; Qrich2 KO mice show reduced tubulin glutamylation and microtubule instability in sperm flagella, dysregulated glutamine/glutamate (Gln/Glu) metabolism with accumulated Gln and reduced Glu, and mislocalization of mitochondrial marker proteins in flagella contributing to reduced mitochondrial function and sperm motility. Dietary Gln/Glu deprivation phenocopied Qrich2 KO mice. Qrich2 KO mouse model, metabolic profiling, tubulin glutamylation assays, mitochondrial localization experiments, dietary intervention rescue experiment Cellular and molecular life sciences : CMLS Medium 38597976
2024 QRICH2 has antioxidant properties that protect spermatids from ROS-induced damage; Qrich2 KO mice show elevated ROS levels, DNA damage in spermatids, increased autophagy and apoptosis, and reduced sperm count. Incubation with purified N-terminal QRICH2 protein exhibited antioxidant activity in vitro, enhancing spermatozoa viability and motility. HE staining, immunofluorescence, flow cytometry, single sperm metabolism analysis in Qrich2 KO mice; in vitro incubation with purified N-terminal QRICH2 protein Reproductive biology Medium 38772286
2023 CFAP70 regulates sperm flagella biogenesis partially by controlling the expression of QRICH2; Cfap70 KO mice show reduced QRICH2 expression levels, placing CFAP70 upstream of QRICH2 in the flagellar assembly pathway. Cfap70 KO mouse model, protein expression analysis EBioMedicine Medium 37352829
2026 Human QRICH2 has no paralogs, is conserved across mammals with two functional domains, is restricted to the testes at the protein level, localizes to different cellular compartments throughout spermatogenesis, and acts as a cytoskeletal component in mature sperm in both the head and flagellum. Mass spectrometry isoform identification, in silico paralog/conservation analysis, immunodetection across 12 human organs, proteomic dataset analysis Reproduction (Cambridge, England) Medium 41575150

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella. Nature communications 128 30683861
2021 Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders. Human reproduction (Oxford, England) 51 34089056
2005 Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1-q25.2. Molecular carcinogenesis 49 15937959
2021 Loss-of-function missense variant of AKAP4 induced male infertility through reduced interaction with QRICH2 during sperm flagella development. Human molecular genetics 35 34415320
2022 Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia. Andrology 33 36017582
2019 Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations. Clinical genetics 29 31292949
2023 CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men. EBioMedicine 22 37352829
2020 Black Raspberry Inhibits Oral Tumors in Mice Treated with the Tobacco Smoke Constituent Dibenzo(def,p)chrysene Via Genetic and Epigenetic Alterations. Cancer prevention research (Philadelphia, Pa.) 18 31969344
2020 Multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes: The relationships between genetic variation and litter size in goats. Gene 16 32439377
2022 A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities. Genetics, selection, evolution : GSE 11 35255804
2022 Further Insights on RNA Expression and Sperm Motility. Genes 11 35886074
2022 Trio-based exome sequencing broaden the genetic spectrum in keratoconus. Experimental eye research 11 36502923
2024 Metabolic profiling identifies Qrich2 as a novel glutamine sensor that regulates microtubule glutamylation and mitochondrial function in mouse sperm. Cellular and molecular life sciences : CMLS 7 38597976
2020 Whole Exome Sequencing of Multiple Atypical Meningiomas in a Patient without History of Neurofibromatosis Type II: A Case Report. The American journal of case reports 5 32461543
2023 Cerebrospinal Fluid Protein Biomarker Discovery in CLN3. Journal of proteome research 4 37338096
2024 Genomics and tumor microenvironment of breast mucoepidermoid carcinoma based on whole-exome and RNA sequencing. Diagnostic pathology 3 38243319
2024 A Key regulatory protein QRICH2 governing sperm function with profound antioxidant properties, enhancing sperm viability. Reproductive biology 3 38772286
2026 Exploring QRICH2 as a potential male contraceptive target. Reproduction (Cambridge, England) 0 41575150
2025 Genetic variants in QRICH2 gene among Jordanians with sperm motility disorders. The Libyan journal of medicine 0 40107860

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