Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness.
X-linked syndromes associated with developmental delay and sensorineural hearing loss (SNHL) have been characterized at the molecular level, including Mohr-Tranebjaerg syndrome and Norrie disease. In this study we report on a novel X-linked recessive, congenital syndrome in a family with developmental delay and SNHL that maps to a locus associated with mental retardation (MR) for which no causative gene has been identified. The X-linked recessive inheritance and congenital nature of the syndrome was confirmed by detailed clinical investigation and the family history. Linkage mapping of the X-chromosome was conducted to ascertain the disease locus and candidate genes were screened by direct sequencing and STRP analysis. The recessive syndrome was mapped to Xp11.3-q21.32 and a deletion was identified in a regulatory region upstream of the POU3F4 gene in affected family members. Since mutations in POU3F4 cause deafness at the DFN3 locus, the deletion is the likely cause of the SNHL in this family. The choroideremia (CHM) gene was also screened and a novel missense change was identified. The alteration changes the serine residue at position 89 in the Rab escort 1 protein (REP-1) to a cysteine (S89C). Prenylation of Rab proteins was investigated in patients and the location of REP-1 expression in the brain determined. However, subsequent analysis revealed that this change in CHM was polymorphic having no effect on REP-1 function. Although the causative gene at the MR locus in this family has not been identified, there are a number of genes involved in syndromic and nonsyndromic forms of MR that are potential candidates.
Hildebrand
Michael S
MS
Department of Otolaryngology, Head and Neck Surgery, University of Iowa, Iowa City, Iowa 52242, USA. michael-hildebrand@uiowa.edu
de Silva
Michelle G
MG
Tan
Tiong Yang
TY
Rose
Elizabeth
E
Nishimura
Carla
C
Tolmachova
Tanya
T
Hulett
Joanne M
JM
White
Susan M
SM
Silver
Jeremy
J
Bahlo
Melanie
M
Smith
Richard J H
RJ
Dahl
Hans-Henrik M
HH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050809:POU Domain Factors / Q000235:genetics; D010375:Pedigree; D017368:Protein Prenylation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D050809:POU Domain Factors; C091774:POU3F4 protein, human