title: Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome.
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 (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.
authors.affiliation: Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
authors.forename: Mercè
authors.initials: M
authors.lastname: Garcia-Barceló
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Danny Ko-Chun
authors.initials: DK
authors.lastname: Lau
authors.forename: Thomas Yuk-Yu
authors.initials: TY
authors.lastname: Leon
authors.forename: Zheng-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Wei-Song
authors.initials: WS
authors.lastname: Cai
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Herbrick
authors.forename: Emily
authors.initials: E
authors.lastname: Gutter
authors.forename: Virginia
authors.initials: V
authors.lastname: Proud
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Pierre-Louis
authors.forename: Kirk
authors.initials: K
authors.lastname: Aleck
authors.forename: Ernest
authors.initials: E
authors.lastname: van Heurn
authors.forename: Elena
authors.initials: E
authors.lastname: Belloni
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: 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*
chemical_list: D018398:Homeodomain Proteins; C490003:MNX1 protein, human; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine