Truncating mutation in the NHS gene: phenotypic heterogeneity of Nance-Horan syndrome in an asian Indian family.
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.
Ramprasad
Vedam Lakshmi
VL
Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
Thool
Alka
A
Murugan
Sakthivel
S
Nancarrow
Derek
D
Vyas
Prateep
P
Rao
Srinivas Kamalakar
SK
Vidhya
Authiappan
A
Ravishankar
Krishnamoorthy
K
Kumaramanickavel
Govindasamy
G
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
D008565:Membrane Proteins; C488621:NHS protein, human; D009687:Nuclear Proteins