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A Homozygosity-Based Search for Mutations in Patients with Autosomal Recessive Retinitis Pigmentosa, Using Microsatellite Markers

¹From the Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, Japan; the ²Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; the ³Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan; the ⁴Department of Ophthalmology and Visual Science, Graduate School of Medicine, Nagoya University, Nagoya, Japan; and the ⁵Hayashi Eye Hospital, Fukuoka, Japan.

PURPOSE. To identify possible mutations in known candidate genes in patients with autosomal recessive (ar) and simplex retinitis pigmentosa (RP), by using an established strategy of flexible, multiplexed, microsatellite-based homozygosity mapping.

METHODS. A total of 78 microsatellite markers corresponding to 16 genes known to be responsible for arRP were selected and used in 18 multiplex amplifications, followed by genotyping. Twelve consanguineous probands and 47 nonconsanguineous probands (59 patients with arRP or simplex RP) agreed to the screening.

RESULTS. Of the 59 probands examined, 24 had a mean of 1.4 genes showing homozygosity for all markers within the corresponding gene region. Subsequent direct sequencing revealed three homozygous mutations. Two of them were novel mutations in the genes TULP1 (c.1145TC, F382S) and CNGB1 (c.3444+1GA). The other was a mutation in RPE65 (c.1543CT, R515W), which is known to cause Leber’s congenital amaurosis. The clinical features of each patient, together with the cosegregation analysis, strongly support the pathogenicity of these mutations.

CONCLUSIONS. This systematic approach facilitated the identification of genes that cause arRP, and the results provide a widened spectrum of the mutation severity associated with a broader range of phenotypic manifestations of arRP.

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