X-linked cataract and Nance-Horan syndrome are allelic disorders.
Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.
UCL Institute of Ophthalmology, London, UK.
Margherita
M
Coccia
Simon P
SP
Brooks
Tom R
TR
Webb
Katja
K
Christodoulou
Izabella O
IO
Wozniak
Victoria
V
Murday
Martha
M
Balicki
Harris A
HA
Yee
Teresia
T
Wangensteen
Ruth
R
Riise
Anand K
AK
Saggar
Soo-Mi
SM
Park
Naheed
N
Kanuga
Peter J
PJ
Francis
Eamonn R
ER
Maher
Anthony T
AT
Moore
Isabelle M
IM
Russell-Eggitt
Alison J
AJ
Hardcastle
D000328:Adult; D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D018628:Gene Dosage; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D055815:Young Adult
D008565:Membrane Proteins; C488621:NHS protein, human; D009687:Nuclear Proteins