Affinage

QRICH2

Glutamine-rich protein 2 · UniProt Q9H0J4

Length
1663 aa
Mass
180.8 kDa
Annotated
2026-04-28
19 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

QRICH2 is a testis-specific cytoskeletal protein essential for sperm flagella biogenesis and male fertility. It stabilizes flagellar development proteins, physically interacts with AKAP4 in the fibrous sheath, and functions as a glutamine sensor that regulates tubulin glutamylation and microtubule integrity in sperm flagella (PMID:30683861, PMID:34415320, PMID:38597976). QRICH2 also possesses intrinsic antioxidant activity that protects spermatids from ROS-induced DNA damage, apoptosis, and autophagy (PMID:38772286). Loss-of-function mutations in QRICH2 cause multiple morphological abnormalities of the sperm flagella (MMAF) syndrome and male infertility in humans, mice, and cattle (PMID:30683861, PMID:35255804).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2019 High

    The fundamental requirement of QRICH2 for sperm flagella formation was established, answering whether this uncharacterized glutamine-rich protein had a specific developmental function; loss-of-function caused MMAF in both mice and human patients, and proteomics revealed QRICH2 stabilizes flagellar development proteins.

    Evidence CRISPR-Cas9 Qrich2 KO mice with proteomic comparison to wild-type testes, confirmed in human MMAF patients

    PMID:30683861

    Open questions at the time
    • Direct molecular targets of QRICH2 stabilization not individually validated
    • Mechanism by which QRICH2 stabilizes flagellar proteins unknown
    • Whether QRICH2 has functions beyond structural stabilization not addressed
  2. 2021 Medium

    The discovery that QRICH2 physically interacts with AKAP4 and co-localizes in the fibrous sheath placed QRICH2 within a specific structural compartment of the flagellum, establishing that its expression depends on AKAP4 levels.

    Evidence Reciprocal Co-IP and immunofluorescence co-localization in sperm; AKAP4 hemizygous loss reduced QRICH2 protein expression

    PMID:34415320

    Open questions at the time
    • Whether the QRICH2-AKAP4 interaction is direct or scaffolded is unresolved
    • Functional consequence of QRICH2 reduction downstream of AKAP4 loss not fully dissected from other fibrous sheath defects
  3. 2022 High

    Cross-species validation in cattle demonstrated that QRICH2 loss-of-function causes MMAF through nonsense-mediated mRNA decay, confirming evolutionary conservation of its essential role in flagella formation.

    Evidence Genome sequencing and testis transcriptome analysis in 76 bulls; homozygous frameshift bulls showed immotile sperm with MMAF

    PMID:35255804

    Open questions at the time
    • Whether specific downstream protein targets are conserved between species not examined
    • No rescue experiment performed in the bovine model
  4. 2023 Medium

    Placing QRICH2 within a regulatory hierarchy, CFAP70 was shown to control QRICH2 expression during flagella biogenesis, linking QRICH2 to cytoplasmic preassembly of axonemal complexes.

    Evidence Cfap70-KO mouse model with protein expression analysis and functional rescue

    PMID:37352829

    Open questions at the time
    • Whether CFAP70 regulates QRICH2 transcriptionally or post-translationally is unclear
    • Single lab finding not independently replicated
  5. 2024 Medium

    Two studies expanded QRICH2 function beyond structural stabilization: it acts as a glutamine sensor regulating tubulin glutamylation and microtubule stability, and independently exhibits antioxidant activity protecting spermatids from ROS-induced damage and apoptosis.

    Evidence Metabolic profiling of Qrich2 KO sperm with dietary Gln/Glu deprivation phenocopy; purified N-terminal QRICH2 protein showing antioxidant activity in vitro; flow cytometry and ROS measurements in KO mice

    PMID:38597976 PMID:38772286

    Open questions at the time
    • The glutamine-sensing domain or mechanism is not structurally defined
    • Whether the antioxidant function maps to a specific domain beyond the N-terminus is unresolved
    • Relationship between glutamine sensing and antioxidant activities not tested
  6. 2026 Medium

    Detailed characterization of human QRICH2 established its exclusive testis expression, dynamic localization during spermatogenesis, and incorporation as a cytoskeletal component in both the sperm head and flagellum, resolving its spatial distribution in mature sperm.

    Evidence Mass spectrometry of human sperm, immunodetection across 12 human organs

    PMID:41575150

    Open questions at the time
    • Functional significance of head localization versus flagellar localization not dissected
    • Which isoforms contribute to which subcellular functions remains untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of QRICH2 function — including how its glutamine-rich domain senses glutamine, which domains mediate protein stabilization versus antioxidant activity, and the complete interactome beyond AKAP4 — remains undefined.
  • No crystal or cryo-EM structure available
  • Full interactome in spermatids/spermatozoa not mapped
  • Whether QRICH2 has catalytic activity or acts as a scaffold for glutamylation enzymes is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0016209 antioxidant activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1474165 Reproduction 2
Partners
AKAP4CFAP70

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 QRICH2 is essential for sperm flagellar formation; loss-of-function mutations cause MMAF phenotype. Proteomic analysis of Qrich2 KO mouse testes demonstrated that QRICH2 stabilizes and enhances expression of proteins related to flagellar development. CRISPR-Cas9 knockout mice, proteomic analysis of KO vs wild-type testes, in vitro experiments Nature communications High 30683861
2021 AKAP4 and QRICH2 interact physically and co-localize in sperm flagella; a hemizygous loss-of-function variant in AKAP4 reduces AKAP4 protein expression, which in turn decreases QRICH2 protein expression in spermatozoa, causing dysplastic fibrous sheath. Co-immunoprecipitation (Co-IP), immunofluorescence co-localization, HEK-293T cell transfection experiments, spermatozoa protein expression analysis Human molecular genetics Medium 34415320
2022 A 1-bp frameshift deletion in bovine QRICH2 causes premature termination and nonsense-mediated mRNA decay, resulting in low sperm count and immotile sperm with multiple morphological abnormalities of the flagellum. Genome sequencing, testis transcriptome analysis (n=76 bulls), semen analysis of homozygous bulls Genetics, selection, evolution : GSE High 35255804
2023 CFAP70 regulates sperm flagella biogenesis partly by controlling expression of QRICH2, and assists cytoplasmic preassembly of the calmodulin- and radial spoke-associated complex (CSC) and manchette localization of axoneme-related proteins. Cfap70-KO mice, protein expression analysis, functional rescue experiments EBioMedicine Medium 37352829
2024 QRICH2 acts as a glutamine sensor in sperm; Qrich2 KO causes dysregulated glutamine/glutamate metabolism (accumulated Gln, reduced Glu), reduced tubulin glutamylation and microtubule instability in sperm flagella, and mislocalization of mitochondrial marker proteins leading to reduced mitochondrial function and sperm motility. Metabolic profiling of Qrich2 KO mouse sperm/testes, tubulin glutamylation assays, dietary Gln/Glu deprivation phenocopy experiments, mitochondrial protein localization studies Cellular and molecular life sciences : CMLS Medium 38597976
2024 QRICH2 has antioxidant function in spermatids; Qrich2 KO elevates ROS levels, causing DNA damage in spermatids, triggering increased autophagy and apoptosis and reduced sperm count. Purified N-terminal QRICH2 protein exhibits antioxidant activity in vitro and enhances 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
2026 Human QRICH2 has no paralogs, is expressed exclusively in testes among 12 human organs, localizes to different cellular compartments during spermatogenesis, and acts as a cytoskeletal component in mature sperm in both the head and flagellum. Mass spectrometry confirmed which QRICH2 isoforms are expressed in human sperm. Mass spectrometry of human sperm, immunodetection across 12 human organs, proteomic dataset analyses, in silico domain 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 127 30683861
2021 Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders. Human reproduction (Oxford, England) 50 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 34 34415320
2022 Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia. Andrology 30 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.) 17 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 Trio-based exome sequencing broaden the genetic spectrum in keratoconus. Experimental eye research 11 36502923
2022 Further Insights on RNA Expression and Sperm Motility. Genes 9 35886074
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