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PATL2 is an oocyte-specific RNA-binding protein whose biallelic mutations cause Oocyte maturation defect 4 (OOMD4), an autosomal recessive disorder defined by arrest of oocyte maturation. Patients with OOMD4 present with germinal vesicle (GV), metaphase I (MI) or metaphase II (MII) arrest leading to female infertility. Initial identification of a homozygous nonsense variant c.784C>T (p.Arg262Ter) in a consanguineous family highlighted PATL2 as a critical determinant of human oocyte maturation (PMID:28965849). Subsequent screening in a cohort of 179 individuals revealed four additional compound heterozygous cases, confirming autosomal recessive inheritance and a spectrum of variant classes including missense, splice, and frameshift alleles.
Expanded mutational analyses in multiple studies have identified novel homozygous and compound heterozygous variants in PATL2 across unrelated families. Two novel missense mutations c.1376C>A (p.Ser459Tyr) and c.1528C>A (p.Pro510Thr) were found in three patients from consanguineous pedigrees, correlating with GV and MI arrest phenotypes and decreased protein expression in vitro (PMID:32048119). A recurrent missense variant c.649T>A (p.Tyr217Asn) and multiple splice and frameshift mutations further expanded the allelic series. A large‐scale exome study of 935 infertile women reported PATL2 variants in 18 probands (1.93% prevalence), including 15 novel alleles, underscoring its contribution to oocyte maturation defects (PMID:38536595).
Functional assays in patient granulosa cells, HeLa and 293T models demonstrate that PATL2 mutations often lead to reduced protein levels via aberrant splicing or impaired ubiquitin‐mediated degradation. Western blot and immunostaining confirm decreased PATL2 abundance in affected oocytes, while minigene splicing assays verify intronic variant effects on mRNA processing (PMID:36072676). Knock‐in and knockout mouse models recapitulate oocyte maturation arrest, and teratoma assays of induced pluripotent stem cells derived from a heterozygous patient exhibit normal pluripotency but highlight the value of stem cell platforms for mechanistic studies (PMID:35397397).
Mechanistically, the PATL2 p.Tyr217Asn mutation inhibits protein ubiquitination, leading to accumulation of PATL2 that aberrantly binds Mos mRNA, dysregulating the MAPK pathway and impairing meiotic progression (PMID:33614659). Phosphoproteomic analysis identified a critical S279 phosphorylation site regulating PATL2 stability, and mouse knock-in of phosphomimetic S279D results in subfertility. These data delineate a loss-of-function mechanism with occasional dominant-negative features depending on variant context.
No studies have refuted the PATL2–OOMD4 association; instead, accumulating case and functional evidence satisfies ClinGen criteria for a definitive gene–disease relationship. PATL2 sequencing should be incorporated into diagnostic panels for female infertility, with implications for genetic counseling, preimplantation genetic testing, and development of targeted therapies.
Key Take-home: Biallelic PATL2 mutations cause autosomal recessive Oocyte maturation defect 4 via loss of RNA-binding function, with robust genetic and functional validation supporting clinical testing and research applications.
Gene–Disease AssociationDefinitiveOver 26 unrelated probands across >15 families with biallelic PATL2 variants, autosomal recessive segregation, concordant functional studies Genetic EvidenceStrong26 probands with homozygous or compound heterozygous PATL2 variants across consanguineous and non-consanguineous families, including nonsense, missense, splice, and frameshift alleles Functional EvidenceStrongIn vitro assays and mouse models demonstrate reduced PATL2 protein, disrupted oocyte maturation, mechanistic insight via Mos-MAPK pathway and phosphorylation studies |