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Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome

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...

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Autores principales: Moreno-Leon, Laura, Quezada-Ramirez, Marco A., Bilsbury, Evan, Kiss, Courtney, Guerin, Andrea, Khanna, Hemant
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437271/
https://www.ncbi.nlm.nih.gov/pubmed/36061204
http://dx.doi.org/10.3389/fgene.2022.982127
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author Moreno-Leon, Laura
Quezada-Ramirez, Marco A.
Bilsbury, Evan
Kiss, Courtney
Guerin, Andrea
Khanna, Hemant
author_facet Moreno-Leon, Laura
Quezada-Ramirez, Marco A.
Bilsbury, Evan
Kiss, Courtney
Guerin, Andrea
Khanna, Hemant
author_sort Moreno-Leon, Laura
collection PubMed
description 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.
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spelling pubmed-94372712022-09-03 Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome Moreno-Leon, Laura Quezada-Ramirez, Marco A. Bilsbury, Evan Kiss, Courtney Guerin, Andrea Khanna, Hemant Front Genet Genetics 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. Frontiers Media S.A. 2022-08-19 /pmc/articles/PMC9437271/ /pubmed/36061204 http://dx.doi.org/10.3389/fgene.2022.982127 Text en Copyright © 2022 Moreno-Leon, Quezada-Ramirez, Bilsbury, Kiss, Guerin and Khanna. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Moreno-Leon, Laura
Quezada-Ramirez, Marco A.
Bilsbury, Evan
Kiss, Courtney
Guerin, Andrea
Khanna, Hemant
Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title_full Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title_fullStr Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title_full_unstemmed Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title_short Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
title_sort prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437271/
https://www.ncbi.nlm.nih.gov/pubmed/36061204
http://dx.doi.org/10.3389/fgene.2022.982127
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