Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
Laura Moreno-Leon1, Marco A Quezada-Ramirez1, Evan Bilsbury1
1Department of Ophthalmology and Visual Sciences, UMass Chan Medical School, Worcester, MA, United States.
Insights
This study identifies a novel RPGRIP1L gene mutation causing Meckel-Gruber Syndrome (MKS). The RPGRIP1L-∆Ex6 variant reduces ciliary localization, offering a potential disease mechanism for this ciliopathy.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Human Pathologies
Background:
- Ciliopathies are inherited disorders arising from defects in cilia, essential cellular organelles.
- Mutations in the RPGRIP1L gene are linked to severe embryonic defects, including Meckel-Gruber Syndrome (MKS).
Purpose of the Study:
- To investigate RPGRIP1L mutations in a family diagnosed with Meckel-Gruber Syndrome.
- To elucidate the functional consequences of a novel RPGRIP1L variant on ciliary function.
Main Methods:
- Genetic analysis of RPGRIP1L in parental DNA samples.
- Functional assessment of a novel RPGRIP1L splice site mutation (RPGRIP1L-∆Ex6) in cultured cells.
- Analysis of ciliary localization of the mutant RPGRIP1L protein.
Main Results:
- Identified a novel splice site mutation (IVS6+1 G > A) in the maternal RPGRIP1L allele, leading to exon 6 exclusion (RPGRIP1L-∆Ex6).
- The father carried a known R1236C mutation in RPGRIP1L.
- The RPGRIP1L-∆Ex6 mutant protein showed reduced localization within cilia in cultured cells.
Conclusions:
- A novel RPGRIP1L variant, RPGRIP1L-∆Ex6, in combination with RPGRIP1L-R1236C, is associated with Meckel-Gruber Syndrome.
- Reduced ciliary localization of RPGRIP1L due to exon 6 deletion suggests a plausible disease mechanism for MKS.
Abstract:
Ciliopathies are a class of inherited severe human disorders that occur due to defective formation or function of cilia. The RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein1-like) gene encodes for a ciliary protein involved in regulating cilia formation and function. Mutations in RPGRIP1L cause ciliopathies associated with severe embryonic defects, such as Meckel-Gruber Syndrome (MKS). Here we report RPGRIP1L mutation analysis in a family diagnosed with MKS. The clinical manifestations of the fetus included thoraco-lumbar open neural tube defect with associated Chiari type II malformation and hydrocephalus, bilateral club feet, and single right kidney/ureter. Analysis of the parental DNA samples revealed that the father carried a previously reported mutation R1236C/+ whereas the mother had a novel splice site mutation IVS6+1 G > A/+ in RPGRIP1L. The splice site mutation resulted in the exclusion of in-frame exon 6 of RPGRIP1L (RPGRIP1L-∆Ex6) but expressed a stable protein in fibroblasts derived from the parents' skin biopsies. The GFP-RPGRIP1L-∆Ex6 mutant protein exhibited relatively reduced ciliary localization in transiently-transfected cultured RPE-1 cells. Taken together, this study identifies a novel RPGRIP1L variant RPGRIP1L-∆Ex6, which in combination with RPGRIP1L-R1236C is associated with MKS. We also suggest that the deletion of exon 6 of RPGRIP1L leads to reduced ciliary localization of RPGRIP1L, indicating a plausible mechanism of associated disease.
