Identification of novel mutations in SEMA4A gene associated with retinal degenerative diseases

Aiysha Abid ¹, Muhammad Ismail ¹, S. Qasim Mehdi ¹ and Shagufta Khaliq ^1*

¹ Biomedical and Genetic Engineering Division, Dr. A. Q. Khan Research Laboratories, Islamabad, Pakistan

^* To whom correspondence should be addressed. E-mail: skhaliq{at}comsats.net.pk.

Accepted 17 September 2005

Abstract

Introduction: SEMA4A is a member of a large transmembrane protein family known as Semaphorins. Disruption in SEMA4A gene has been reported to be associated with severe retinal degeneration in a mouse model. To date no study has been published showing an association between SEMA4A gene mutations and human retinal degeneration. This study was carried out to investigate the association of SEMA4A gene with the human retinal degenerations.

Methods: A panel of 190 unrelated patients suffering from various retinal diseases, including RP, CRD and LCA was collected. To identify disease-associated mutations in the SEMA4A gene, DNA samples of patients were screened by SSCP, followed by direct DNA sequencing.

,Results: We found a heterozygous G to C change (D345H) and a heterozygous T to G change (F350C), co-segregating in two RP and two CRD patients. Another heterozygous G to A mutation (R713Q) was found in three RP patients and a patient with congenital blindness. Besides these disease-causing mutations several non-pathogenic changes were also found, including a 2 base pair deletion at 26bp down stream of exon 10 and three isocoding single base pair substitution.

Discussion: Identification of four heterozygous mutations including a compound heterozygous mutation suggest an autosomal dominant type of retinal degeneration associated with the mutations in SEMA4A gene. This is the first report of the involvement of the SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD) in humans. Further biochemical studies are needed to be done to elucidate the role of this gene in the disease mechanism.

Keywords: SEMA4A, cone rod dystrophy, retinal degeneration, retinitis pigmentosa

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