title: CNGA3 mutations in hereditary cone photoreceptor disorders.
abstract: We recently showed that mutations in the CNGA3 gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all detected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Scandinavia and northern Italy, have a common origin.
authors.affiliation: Molekulargenetisches Labor, Abt Pathophysiologie des Sehens und Neuroophthalmologie, Tübingen, Germany. wissinger@uni-tuebingen.de wissinger@uni-tuebingen.de
authors.forename: B
authors.initials: B
authors.lastname: Wissinger
authors.forename: D
authors.initials: D
authors.lastname: Gamer
authors.forename: H
authors.initials: H
authors.lastname: Jägle
authors.forename: R
authors.initials: R
authors.lastname: Giorda
authors.forename: T
authors.initials: T
authors.lastname: Marx
authors.forename: S
authors.initials: S
authors.lastname: Mayer
authors.forename: S
authors.initials: S
authors.lastname: Tippmann
authors.forename: M
authors.initials: M
authors.lastname: Broghammer
authors.forename: B
authors.initials: B
authors.lastname: Jurklies
authors.forename: T
authors.initials: T
authors.lastname: Rosenberg
authors.forename: S G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: E C
authors.initials: EC
authors.lastname: Sener
authors.forename: S
authors.initials: S
authors.lastname: Tatlipinar
authors.forename: C B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: C
authors.initials: C
authors.lastname: Castellan
authors.forename: P
authors.initials: P
authors.lastname: Bitoun
authors.forename: S
authors.initials: S
authors.lastname: Andreasson
authors.forename: G
authors.initials: G
authors.lastname: Rudolph
authors.forename: U
authors.initials: U
authors.lastname: Kellner
authors.forename: B
authors.initials: B
authors.lastname: Lorenz
authors.forename: G
authors.initials: G
authors.lastname: Wolff
authors.forename: C
authors.initials: C
authors.lastname: Verellen-Dumoulin
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
authors.forename: F P
authors.initials: FP
authors.lastname: Cremers
authors.forename: E
authors.initials: E
authors.lastname: Apfelstedt-Sylla
authors.forename: E
authors.initials: E
authors.lastname: Zrenner
authors.forename: R
authors.initials: R
authors.lastname: Salati
authors.forename: L T
authors.initials: LT
authors.lastname: Sharpe
authors.forename: S
authors.initials: S
authors.lastname: Kohl
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D054815:Cyclic Nucleotide-Gated Cation Channels; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011487:Protein Conformation; D017949:Retinal Cone Photoreceptor Cells / Q000002:abnormalities*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels