In-frame Three Base Pair Deletion Causes Achromatopsia disease in Six Palestinian Families

Abstract

Achromatopsia is a rare autosomal recessive disease that affects vision and leads to total color blindness. Achromatopsia patients suffer from photophobia, nystagmus, cataracts, reduced visual acuity, and eccentric fixation. The disease has been demonstrated to result from mutations in four different genes, CNGB3, CNGA3, GNAT2, and PDE6C. Although achromatopsia is very rare disorder, it is frequently found in some areas of the world such as Iraq, Morocco, Iranian Jews(Zlotogora, 1995), it also is present throughout the world with varying incidence according to the geographical area. From the last decade till today, extraordinary research studies have been applied to discover the genetic basis of the disease. The purpose of our study is to discover the genetic causes of achromatopsiain the Palestinian families suffering from disease. Methods: Six Palestinian families with achromatopsia were recruited for our study; the affected individuals, their parents and their unaffected siblings were ascertained. Linkage exclusion approach was undertaken to identify the causative gene/s in our families. Sequence analysis of the coding region of the gene/s that we failed to exclude its linkage to the disease in a particular family to pinpoint the causative mutation(s) was performed. All identified mutations were tested for segregation with the phenotype in the families and screened in other families with the same phenotype. iv Results: The initial results of linkage exclusion in an extended family revealed that CNGA3, which codes for a cyclic nucleotide-gated cation channel alpha 3 in cone photo receptors in retina, is most likely the responsible gene for achromatopsia. Sequencing of all coding exons of this gene revealed an in-frame three base pair deletion, resulting in deletion of isoleucine 312, which seems to be critical for the integrity of transmembrane domains of this photoreceptor. Sanger sequencing results revealed that this deletion perfectly segregates with the phenotype in all of the six families in autosomal recessive mode of inheritance. Conclusion: An in-frame three base pair deletion in exon 8 of CNGA3 gene was identified in a homozygous form in all affected members in all six Palestinian families with achromatopsia in our study. This gene has been shown to cause achromatopsia in people from different ethnic backgrounds. Key words: Achromatopsia, linkage exclusion, homozygous, cyclic nucleotide gated channel alpha 3 (CNGA3).