Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome.
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.
Garcia-Barceló
Mercè
M
Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
So
Man-Ting
MT
Lau
Danny Ko-Chun
DK
Leon
Thomas Yuk-Yu
TY
Yuan
Zheng-Wei
ZW
Cai
Wei-Song
WS
Lui
Vincent Chi-Hang
VC
Fu
Ming
M
Herbrick
Jo-Anne
JA
Gutter
Emily
E
Proud
Virginia
V
Li
Long
L
Pierre-Louis
Jacqueline
J
Aleck
Kirk
K
van Heurn
Ernest
E
Belloni
Elena
E
Scherer
Stephen W
SW
Tam
Paul Kwong-Hang
PK
D000015:Abnormalities, Multiple / Q000235:genetics*; D001003:Anal Canal / Q000002:abnormalities*; D005260:Female; D005828:Genetics, Population; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010455:Peptides / Q000235:genetics; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012447:Sacrum / Q000002:abnormalities*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C490003:MNX1 protein, human; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine