Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome

Mercè Garcia-Barceló, Man Ting So, Danny Ko Chun Lau, Thomas Yuk Yu Leon, Zheng Wei Yuan, Wei Song Cai, Vincent Chi Hang Lui, Ming Fu, Jo Anne Herbrick, Emily Gutter, Virginia Proud, Long Li, Jacqueline Pierre-Louis, Kirk Aleck, Ernest Van Heurn, Elena Belloni, Stephen W. Scherer, Paul Kwong Hang Tam

Research output: Contribution to journalArticle

Abstract

Background: The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in HLXB9. Methods: We analyzed 5 CS families and 6 sporadic cases for HLXB9 mutations by direct sequencing. Potentially pathologic expansions of HLXB9 GCC repeats were analyzed in patients, 4 general populations [Chinese, Japanese, Yoruba, and Centre du Etude Polymorphisme Human (CEPH)] from the HapMap project, and 145 healthy Chinese. Results: We identified 6 novel mutations affecting highly conserved residues (Serl85X, Trp215X, Ala26fs, Ala75/s, Met1Ile, and Arg273Cys). GCC allele and genotype distributions showed marked statistically significant differences. (GCC)11 was the most common allele overall; its frequency ranged from 90% in CEPH to 68% in Yoruba and 50% in Chinese and Japanese populations. (GCC)9 was almost as common as (GCC)11 in Chinese and Japanese populations, whereas its frequency was 12 and (GCC) 13], which were almost absent in the other groups. Conclusions: Lack of HLXB9 mutations in some patients and the presence of variable phenotypes suggest DNA alterations in HLXB9 noncoding regions and/or in other genes encoding HLXB9 regulatory molecules or protein partners. If HLXB9, like other homeobox genes, has a threshold beyond which triplet expansions are pathologic, those populations enriched with larger alleles would be at a higher risk. The data illustrate the importance of ethnicity adjustment if these polymorphic markers are to be used in association studies.

Original languageEnglish
Pages (from-to)46-52
Number of pages7
JournalClinical Chemistry
Volume52
Issue number1
DOIs
Publication statusPublished - Jan 2006

ASJC Scopus subject areas

  • Clinical Biochemistry

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    Garcia-Barceló, M., So, M. T., Lau, D. K. C., Leon, T. Y. Y., Yuan, Z. W., Cai, W. S., Lui, V. C. H., Fu, M., Herbrick, J. A., Gutter, E., Proud, V., Li, L., Pierre-Louis, J., Aleck, K., Van Heurn, E., Belloni, E., Scherer, S. W., & Tam, P. K. H. (2006). Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome. Clinical Chemistry, 52(1), 46-52. https://doi.org/10.1373/clinchem.2005.056192