title: Truncating mutation in the NHS gene: phenotypic heterogeneity of Nance-Horan syndrome in an asian Indian family.
abstract: OBJECTIVE
  A four-generation family containing eight affected males who inherited X-linked developmental lens opacity and microcornea was studied. Some members in the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. The purpose of the study was to map genetically the gene in the large 57-live-member Asian-Indian pedigree.
  
  
  METHODS
  PCR-based genotyping was performed on the X-chromosome, by using fluorescent microsatellite markers (10-cM intervals). Parametric linkage analysis was performed by using two disease models, assuming either recessive or dominant X-linked transmission by the MLINK/ILINK and FASTLINK (version 4.1P) programs (http:www.hgmp.mrc.ac.uk/; provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK). The NHS gene at the linked region was screened for mutation.
  
  
  RESULTS
  By fine mapping, the disease gene was localized to Xp22.13. Multipoint analysis placed the peak LOD of 4.46 at DSX987. The NHS gene mapped to this region. Mutational screening in all the affected males and carrier females (heterozygous form) revealed a truncating mutation 115C-->T in exon 1, resulting in conversion of glutamine to stop codon (Q39X), but was not observed in unaffected individuals and control subjects. conclusions. A family with X-linked Nance-Horan syndrome had severe ocular, but mild to moderate nonocular, features. The clinical phenotype of the truncating mutation (Q39X) in the NHS gene suggests allelic heterogeneity at the NHS locus or the presence of modifier genes. X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.
authors.affiliation: Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Vedam Lakshmi
authors.initials: VL
authors.lastname: Ramprasad
authors.forename: Alka
authors.initials: A
authors.lastname: Thool
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Murugan
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.forename: Prateep
authors.initials: P
authors.lastname: Vyas
authors.forename: Srinivas Kamalakar
authors.initials: SK
authors.lastname: Rao
authors.forename: Authiappan
authors.initials: A
authors.lastname: Vidhya
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Ravishankar
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Kumaramanickavel
mesh_terms: D000293:Adolescent; D000328:Adult; D002386:Cataract / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D005091:Exons; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007194:India; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins; D018895:Microsatellite Repeats; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D008565:Membrane Proteins; C488621:NHS protein, human; D009687:Nuclear Proteins