title: Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis.
abstract: OBJECTIVE
  The purpose of this study was to determine the frequency and spectrum of inosine monophosphate dehydrogenase type I (IMPDH1) mutations associated with autosomal dominant retinitis pigmentosa (RP), to determine whether mutations in IMPDH1 cause other forms of inherited retinal degeneration, and to analyze IMPDH1 mutations for alterations in enzyme activity and nucleic acid binding.
  
  
  METHODS
  The coding sequence and flanking intron/exon junctions of IMPDH1 were analyzed in 203 patients with autosomal dominant RP (adRP), 55 patients with autosomal recessive RP (arRP), 7 patients with isolated RP, 17 patients with macular degeneration (MD), and 24 patients with Leber congenital amaurosis (LCA). DNA samples were tested for mutations by sequencing only or by a combination of single-stranded conformational analysis and by sequencing. Production of fluorescent reduced nicotinamide adenine dinucleotide (NADH) was used to measure enzymatic activity of mutant IMPDH1 proteins. The affinity and the specificity of mutant IMPDH1 proteins for single-stranded nucleic acids were determined by filter-binding assays.
  
  
  RESULTS
  Five different IMPDH1 variants, Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, and His 372Pro, were identified in eight autosomal dominant RP families. Two additional IMPDH1 variants, Arg105Trp and Asn198Lys, were found in two patients with isolated LCA. None of the novel IMPDH1 mutants identified in this study altered the enzymatic activity of the corresponding proteins. In contrast, the affinity and/or the specificity of single-stranded nucleic acid binding were altered for each IMPDH1 mutant except the Gly324Asp variant.
  
  
  CONCLUSIONS
  Mutations in IMPDH1 account for approximately 2% of families with adRP, and de novo IMPDH1 mutations are also rare causes of isolated LCA. This analysis of the novel IMPDH1 mutants substantiates previous reports that IMPDH1 mutations do not alter enzyme activity and demonstrates that these mutants alter the recently identified single-stranded nucleic acid binding property of IMPDH. Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration.
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX 77030, USA. sara.j.bowne@uth.tmc.edu
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mortimer
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhu
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Spellicy
authors.forename: Anisa I
authors.initials: AI
authors.lastname: Gire
authors.forename: Dianna
authors.initials: D
authors.lastname: Hughbanks-Wheaton
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001766:Blindness / Q000151:congenital* / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D012174:Retinitis Pigmentosa / Q000235:genetics*; D020080:Tandem Repeat Sequences
chemical_list: D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human