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Lookup NU author(s): Dr Donna Hagan, Alison Ross, Professor Tom Strachan, Dr Victor Ruiz-Perez, Emerita Professor Susan Lindsay
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The HLXB9 homeobox gene was recently identified as a locus for autosomal dominant Currarino syndrome, also known as hereditary sacral agenesis (HSA). This gene specifies a 403-amino acid protein containing a homeodomain preceded by a very highly conserved 82-amino acid domain of unknown function; the remainder of the protein is not well conserved. Here we report an extensive mutation survey that has identified mutations in the HLXB9 gene in 20 of 21 patients tested with familial Currarino syndrome. Mutations were also detected in two of seven sporadic Currarino syndrome patients; the remainder could be explained by undetected mosaicism for an HLXB9 mutation or by genetic heterogeneity in the sporadic patients. Of the mutations identified in the 22 index patients, 19 were intragenic and included 11 mutations that could lead to the introduction of a premature termination codon. The other eight mutations were missense mutations that were significantly clustered in the homeodomain, resulting, in each patient, in nonconservative substitution of a highly conserved amino acid. All of the intragenic mutations were associated with comparable phenotypes. The only genotype-phenotype correlation appeared to be the occurrence of developmental delay in the case of three patients with microdeletions. HLXB9 expression was analyzed during early human development in a period spanning Carnegie stages 12-21. Signal was detected in the basal plate of the spinal cord and hindbrain and in the pharynx, esophagus, stomach, and pancreas. Significant spatial and temporal expression differences were evident when compared with expression of the mouse Hlxb9 gene, which may partly explain the significant human-mouse differences in mutant phenotype.
Author(s): Lindsay S; Strachan T; Ruiz-Perez V; Hagan DM; Ross AJ; Hassan S; Muenke M; Nixon P; Papapetrou C; Winter RM; Edwards Y; Morrison K; Barrow M; Cordier-Alex MP; Correia P; Galvin-Parton PA; Gaskill S; Gaskin KJ; Garcia-Minaur S; Gereige R; Hayward R; Homfray T; McKeown C; Murday V; Plauchu H; Shannon N; Spitz L; Lynch SA; Wang YM; Scambler P; Custard E; Reardon W
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2000
Volume: 66
Issue: 5
Pages: 1504-1515
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1086/302899
DOI: 10.1086/302899
PubMed id: 10749657
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