RPGRIP1L – Meckel Syndrome Type 5

RPGRIP1L is implicated in Meckel syndrome Type 5 (MKS5), a severe autosomal recessive ciliopathy characterized by occipital encephalocele, polydactyly, and cystic kidney dysplasia.

Biallelic loss-of-function and splice-site variants in RPGRIP1L have been reported in eight unrelated MKS5 probands, expanding the variant spectrum to include truncating (e.g., c.427C>T (p.Gln143Ter)) and intronic splice variants (c.1351-11A>G) with confirmed frameshifts and premature stop codons (PMID:35233738).

Autosomal recessive segregation has been demonstrated in multiple families, including a Chinese kindred with compound heterozygous truncating and splice variants, consistent with loss-of-function inheritance and complete penetrance of the lethal phenotype.

Functional studies in Rpgrip1l-null mice recapitulate the cerebral, renal, and hepatic defects of human MKS5, and show that RPGRIP1L localizes to the ciliary transition zone where it regulates proteasomal activity and sonic hedgehog signaling at the basal body (PMID:17558409).

Mechanistically, RPGRIP1L deficiency disrupts ciliary gating and protein degradation, leading to multiorgan dysplasia and embryonic lethality. These experimental data concord with the human phenotype.

Together, robust genetic evidence from at least eight probands and concordant animal models support a Strong gene–disease association for RPGRIP1L in MKS5. Clinical testing for RPGRIP1L variants informs prenatal diagnosis, genetic counseling, and reproductive planning via PGT-M for families at risk.

References

• Nature genetics • 2007 • The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. PMID:17558409
• Reproductive sciences (Thousand Oaks, Calif.) • 2022 • Identification of Pathogenic Variants in RPGRIP1L with Meckel Syndrome and Preimplantation Genetic Testing in a Chinese Family. PMID:35233738

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