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

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.

• Authors: Muhammad Ajmal, Muhammad Imran Khan, Kornelia Neveling, Yar Muhammad Khan, Maleeha Azam, Nadia Khalida Waheed, Christian P Hamel, Tamar Ben-Yosef, Elfride De Baere, Robert K Koenekoop, Rob W J Collin, Raheel Qamar, Frans P M Cremers
• Journal: Journal of medical genetics (J Med Genet) Vol. 51 Issue 7 Pg. 444-8 (Jul 2014) ISSN: 1468-6244 [Electronic] England
• PMID: 24737827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• RNA Splicing Factors
• DHX38 protein, human
• DEAD-box RNA Helicases

Topics

• Base Sequence
• Coloboma (genetics)
• DEAD-box RNA Helicases (genetics)
• DNA Mutational Analysis
• Female
• Genes, Recessive
• Genetic Association Studies
• Genetic Linkage
• Genetic Predisposition to Disease
• Humans
• Macula Lutea (abnormalities)
• Male
• Mutation, Missense
• Pedigree
• Polymorphism, Single Nucleotide
• RNA Splicing Factors
• Retinitis Pigmentosa (genetics)