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

Clin Chem. 2006 Jan;52(1):46-52. doi: 10.1373/clinchem.2005.056192. Epub 2005 Oct 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Anal Canal / abnormalities*
  • Female
  • Genetics, Population
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Peptides / genetics
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • Sacrum / abnormalities*
  • Syndrome
  • Transcription Factors / genetics*

Substances

  • Homeodomain Proteins
  • MNX1 protein, human
  • Peptides
  • Transcription Factors
  • polyalanine