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J Med Genet. 2014 Jul;51(7):444-8. doi: 10.1136/jmedgenet-2014-102316. Epub 2014 Apr 15.

A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma.

Author information

1
Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Chemistry, University of Science and Technology, Bannu, Pakistan.
4
Department of Ophthalmology, Tufts University School of Medicine, Boston, USA.
5
Department of Genetics, Institut National de la Santé et de la Recherche Médicale U, Université Paris Descartes-Sorbonne Paris Cité, Montpellier, France.
6
Department of Genetics, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
7
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
8
Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Canada.
9
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
10
Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
11
Faculty of Science, Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Abstract

BACKGROUND:

Retinitis pigmentosa (RP) is the most frequent inherited retinal disease, which shows a relatively high incidence of the autosomal-recessive form in Pakistan.

METHODS:

Genome-wide high-density single-nucleotide polymorphism (SNP) microarrays were used to identify homozygous regions shared by affected individuals of one consanguineous family. DNA of three affected and two healthy siblings was used for SNP genotyping. Genotyping data were then analysed by Homozygosity Mapper. DNA of the proband was further analysed employing exome sequencing.

RESULTS:

Homozygosity mapping revealed a single homozygous region on chromosome 16, shared by three affected individuals. Subsequent exome sequencing identified a novel missense mutation, c.995G>A; p.(Gly332Asp), in DHX38. This mutation was found to be present in a homozygous state in four affected individuals while two healthy siblings and the parents of the affected persons were heterozygous for this mutation. This variant thereby yields a logarithm of the odds (LOD) score of 3.25, which is highly suggestive for linkage. This variant was neither detected in 180 ethnically matched control individuals, nor in 7540 Africans or Caucasians and an in-house database that contained the exome data of 400 individuals.

CONCLUSIONS:

By combining genome-wide homozygosity mapping and exome sequencing, a novel missense mutation was identified in the DHX38 gene that encodes the pre-mRNA splicing factor PRP16, in a Pakistani family with early-onset autosomal-recessive RP. The phenotype is different from those associated with other retinal pre-mRNA splicing factors and DHX38 is the first pre-mRNA splicing gene that is putatively associated with autosomal-recessive inherited RP.

PMID:
24737827
DOI:
10.1136/jmedgenet-2014-102316
[Indexed for MEDLINE]
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