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.
Coccia
Margherita
M
UCL Institute of Ophthalmology, London, UK.
Brooks
Simon P
SP
Webb
Tom R
TR
Christodoulou
Katja
K
Wozniak
Izabella O
IO
Murday
Victoria
V
Balicki
Martha
M
Yee
Harris A
HA
Wangensteen
Teresia
T
Riise
Ruth
R
Saggar
Anand K
AK
Park
Soo-Mi
SM
Kanuga
Naheed
N
Francis
Peter J
PJ
Maher
Eamonn R
ER
Moore
Anthony T
AT
Russell-Eggitt
Isabelle M
IM
Hardcastle
Alison J
AJ
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