Novel mutations in MERTK associated with childhood onset rod-cone dystrophy.

Abstract

PURPOSE:

To report the clinical phenotype in patients with a retinal dystrophy associated with novel mutations in the MER tyrosine kinase (MERTK) gene.

METHODS:

A consanguineous family of Middle Eastern origin was identified, and affected members underwent a full clinical evaluation. Linkage analysis was performed using the Affymetrix 50K chip. Regions of homozygosity were identified. The positional candidate genes protocadherin 21 (PCDH21), retinal G protein-coupled receptor (RGR), and MERTK were polymerase chain reaction (PCR) amplified and sequenced. Long-range PCR was performed to characterize the deletion. Two hundred and ninety-two probands with autosomal recessive, childhood onset, retinal dystrophies were analyzed using the Asper Ophthalmics Leber congenital amaurosis chip to screen for known MERTK mutations.

RESULTS:

Analysis of a 50K-Affymetrix whole genome scan identified three regions of homozygosity on chromosomes 2 and 10. Screening of the candidate gene MERTK showed a possible deletion of exon 8. Long-range PCR identified a ~9 kb deletion within MERTK that removes exon 8. Screening of DNA from a panel of Saudi Arabian patients with autosomal recessive retinitis pigmentosa identified a second consanguineous family with the same mutation. One patient with a known MERTK mutation (p.R651X) was identified using the Asper Ophthalmics Leber congenital amaurosis chip. Further screening of the gene identified a second novel splice site mutation in intron 1. The phenotype associated with these identified MERTK mutations is of a childhood onset rod-cone dystrophy with early macular atrophy. The optical coherence tomography (OCT) appearance is distinctive with evidence of debris beneath the sensory retina.

CONCLUSIONS:

Mutations in MERTK are a rare cause of retinal dystrophy. Non homologous recombination between Alu Y repeats near or within disease genes may be an important cause of retinal dystrophies.

• Authors: Donna S Mackay, Robert H Henderson, Panagiotis I Sergouniotis, Zheng Li, Phillip Moradi, Graham E Holder, Naushin Waseem, Shomi S Bhattacharya, Mohammed A Aldahmesh, Fowzan S Alkuraya, Brian Meyer, Andrew R Webster, Anthony T Moore
• Journal: Molecular vision (Mol Vis) Vol. 16 Pg. 369-77 (Mar 09 2010) ISSN: 1090-0535 [Electronic] United States
• PMID: 20300561 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• MERTK protein, human
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase

Topics

• Adolescent
• Adult
• Age of Onset
• Child
• DNA Mutational Analysis
• Electrophoresis, Agar Gel
• Exons (genetics)
• Family
• Female
• Fundus Oculi
• Genetic Predisposition to Disease
• Genome, Human (genetics)
• Haplotypes (genetics)
• Humans
• Leber Congenital Amaurosis (enzymology, genetics)
• Male
• Mutation (genetics)
• Pedigree
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide (genetics)
• Proto-Oncogene Proteins (genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• Retinitis Pigmentosa (enzymology, epidemiology, genetics)
• Young Adult
• c-Mer Tyrosine Kinase