Noncoding RNAs in mental retardation.

Recent genome-wide interrogations of transcribed RNA have yielded compelling evidence for pervasive and complex transcription throughout a large majority of the human genome. Tens of thousands of noncoding RNA transcripts have been identified, most of which have yet to be functionally characterized. Along with the revelation that noncoding RNAs in the human genome are surprisingly abundant, there has been a surge in molecular and genetic data showing important and diverse regulatory roles for noncoding RNA. In this report, we summarize the potential roles that noncoding RNAs may play in the molecular pathogenesis of different mental retardation disorders. We suspect that these findings are just the tip of the iceberg, with noncoding RNAs possibly being involved in disease pathogenesis at different levels and through multiple distinct mechanisms.

Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein.

Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed "SOST." Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.