title: Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1.
abstract: OBJECTIVE
  Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.
  
  
  METHODS
  Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.
  
  
  RESULTS
  The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 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 the 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 ophthalmic examination. This sequence variant was found in 6 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 the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.
authors.affiliation: Department of Medical Biosciences/Medical and Clinical Genetics, University of Umeå, Umeå, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Köhn
authors.forename: Marie S I
authors.initials: MS
authors.lastname: Burstedt
authors.forename: Frida
authors.initials: F
authors.lastname: Jonsson
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kadzhaev
authors.forename: Eneli
authors.initials: E
authors.lastname: Haamer
authors.forename: Ola
authors.initials: O
authors.lastname: Sandgren
authors.forename: Irina
authors.initials: I
authors.lastname: Golovleva
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D001120:Arginine; D030741:Carbonic Anhydrase IV / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003596:Cytosine; D005260:Female; D005654:Fundus Oculi; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013941:Thymine; D014364:Tryptophan
chemical_list: C020932:11-cis-retinal-binding protein; D002352:Carrier Proteins; D014364:Tryptophan; D003596:Cytosine; D001120:Arginine; D030741:Carbonic Anhydrase IV; D013941:Thymine