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Vitamin D Receptor in Idiopathic Short Stature« Back to Volume 23, Issue 1, March 2007 - Table of Contents Stature is a highly heritable trait, but beyond those genes known to cause specific disorders in which short stature is a major component, the genetic factors responsible for variation in height are poorly understood. As reported by Dempfle et al, genome-wide linkage scans of adult height have been performed in at least 22 separate samples and the results summarized in 12 publications. Although these studies, most of which have been performed on relatively small samples, yielded divergent results and no chromosomal region was highlighted across all scans, evidence for linkage is convincing for some regions, in particular regions on chromosomes 6, 7, 9, and 12. Building on these studies, Dempfle et al carried out a genome-wide scan on 92 families, each with 2 affected children with idiopathic short stature (ISS), which they defined as including constitutional delay of growth and puberty, familial short stature, and ISS in its more narrow meaning. For inclusion, each family had one child whose height was below the 5th percentile and a second child with height less than the 15th percentile. Only Caucasian families were included, and all but 2 parents were of German origin. Linkage analysis using 511 short tandem repeat markers revealed the highest LOD score (3.18 [and only LOD score >3]), which is usually accepted proof of linkage, at chromosome 12q11. This is the region to which adult height has been linked and which contains the vitamin D receptor (VDR) gene that has been previously implicated as a factor in adult height variability. In fact, as noted in a 2005 GGH abstract,1 a single nucleotide polymorphism (SNP) at the VDR locus has been associated with variation in adult stature. The same association was found in ISS in this investigation. The VDR polymorphism involves the substitution of a G base for an A base at a particular nucleotide; it is called the G allele. The G allele was detected more often than the A allele in children and adolescents with ISS. The substitution maps to the VDR start codon where it abolishes the first translation initiation site, resulting in a peptide lacking 3 amino acids, which increases the transcriptional activity of the gene. The more active allele was over-transmitted to affected children in the sample giving estimates of relative risks for ISS of 1.33 and 1.9, respectively, for heterozygotes and homozygotes for the allele. The authors suggested that on the population level, the G allele might be responsible for 34% of ISS cases. The genomic scan did not detect evidence of linkage to other sites that have been implicated by other investigators in ISS, including the SHOX and NPR2 loci. Editor’s CommentReaders may ask: if linkage to the VDR locus and association with the G allele of VDR has been established for adult height, why repeat the genomic scan in children with ISS? The reason is that the findings in the adult study could be explained by the effects of several genes, each having a small impact on stature or a small number of genes having a larger impact. Finding a similar effect in a small subset of individuals, ie, those with ISS, argues for a larger effect of a smaller number of genes, of which VDR is one. The next step will be to delineate how the more transcriptionally active VDR allele actually affects linear bone growth. William A. Horton, MD Reference - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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