CARRIER OF R14W IN CARBONIC ANHYDRASE IV PRESENTS BOTHNIA DYSTROPHY PHENOTYPE CAUSED BY TWO ALLELIC MUTATIONS IN RLBP1

¹ Medical Biosciences, University Hospital, Medical and Clinical Genetics, Umea, Sweden
² Clinical Sciences, University Hospital, Ophthalmology, Umea, Sweden
³ Asper Biotech, Tartu, Estonia

^* To whom correspondence should be addressed. E-mail: Irina.Golovleva{at}medbio.umu.se.

	Abstract

PURPOSE. Bothnia dystrophy (BD) is autosomal recessive retinitis pigmentosa (arRP) associated with c.700C>T mutation in RLBP1 gene. Testing of BD patients revealed the c.700C>T mutation on one or both alleles. The aim of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous BD patients. METHODS. BD patients heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer extension technology. Further mutation detection was performed by PCR-RFLP, sequencing, dHLPC and allelic discrimination. The ophthalmic examinations were done in all c.700C>T heterozygotes. RESULTS. The clinical findings in 10 BD heterozygotes were similar to those in homozygotes. Presence of a second mutation, c.677T>A corresponding to p.M226K was detected in all ten cases. Segregation analysis showed that the mutations were allelic and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmologic examination. This sequence variant was found in 6 out of 143 tested blood donors. CONCLUSIONS. The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene, c.677T>A and c.700C>T. BD is caused by loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. CAIV p.R14W sequence variant found in one of the patients with BD phenotype is a benign polymorphism in population of northern Sweden.

Key Words: genetic diseases, visual pigment genes, mutation screening, retinitis pigmentosa, carbonic anhydrase

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