TY - JOUR
T1 - Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome
AU - Garcia Barcelo, M.
AU - So, M.T.
AU - Lau, D.K.
AU - Leon, T.Y.
AU - Yuan, Z.W.
AU - Cai, W.S.
AU - Lui, V.C.
AU - Fu, M.
AU - Herbrick, J.A.
AU - Gutter, E.
AU - Proud, V.
AU - Li, L.
AU - Pierre Louis, J.
AU - Aleck, K.
AU - van Heurn, L.W.E.
AU - Belloni, E.
AU - Scherer, S.W.
AU - Tam, P.K.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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 (Ser185X, Trp215X, Ala26fs, Ala75fs, 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 <10% in Yoruba and CEPH populations. The Yoruba population had the highest frequency of the largest alleles [(GCC)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.
AB - 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 (Ser185X, Trp215X, Ala26fs, Ala75fs, 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 <10% in Yoruba and CEPH populations. The Yoruba population had the highest frequency of the largest alleles [(GCC)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.
U2 - 10.1373/clinchem.2005.056192
DO - 10.1373/clinchem.2005.056192
M3 - Article
C2 - 16254195
SN - 0009-9147
VL - 52
SP - 46
EP - 52
JO - Clinical Chemistry
JF - Clinical Chemistry
IS - 1
ER -