A mutation in IFT43 causes non-syndromic recessive retinal degeneration

The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffe...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 2017-12, Vol.26 (23), p.4741-4751
Main Authors: Biswas, Pooja, Duncan, Jacque L, Ali, Muhammad, Matsui, Hiroko, Naeem, Muhammad Asif, Raghavendra, Pongali B, Frazer, Kelly A, Arts, Heleen H, Riazuddin, Sheikh, Akram, Javed, Hejtmancik, J Fielding, Riazuddin, S Amer, Ayyagari, Radha
Format: Article
Language:English
Subjects:
Base Sequence
Carrier Proteins - genetics
Carrier Proteins - metabolism
Consanguinity
Exome
Exome Sequencing - methods
Female
Genes, Recessive
Homozygote
Humans
Male
Mutation
Pedigree
Phenotype
Retina - metabolism
Retina - physiology
Retinal Degeneration - genetics
Retinal Degeneration - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P 
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddx356