Highly conserved non-coding sequences and the 18q critical region for short stature: a common mechanism of disease?

• Published in: PloS one 2008-01, Vol.3 (1), p.e1460-e1460
• Main Authors: Rizzolio, Flavio, Bione, Silvia, Sala, Cinzia, Tribioli, Carla, Ciccone, Roberto, Zuffardi, Orsetta, di Iorgi, Natascia, Maghnie, Mohamad, Toniolo, Daniela
• Format: Article
• Language: English
• Subjects: Animals; Body Height - genetics; Child, Preschool; Chromosome 18; Chromosome rearrangements; Chromosomes; Chromosomes, Human, Pair 18; Development and progression; Developmental Biology/Molecular Development; Disorders; Embryogenesis; Embryonic development; Embryonic Development - genetics; Embryonic growth stage; Enhancers; Etiology; Gene expression; Genes; Genetic aspects; Genetics; Genetics and Genomics/Bioinformatics; Genetics and Genomics/Epigenetics; Genetics and Genomics/Functional Genomics; Genetics and Genomics/Medical Genetics; Genomics; Genotype & phenotype; Growth hormone; Growth hormones; Humans; Hypotheses; In Situ Hybridization, Fluorescence; Male; Medical research; Mice; Mutation; NMR; Nuclear magnetic resonance; Patients; Pediatrics; Pituitary; Pituitary hormones; Regulatory sequences; Short stature; Silencers; Somatotropin; Translocation; X Chromosomes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001460

Isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) are heterogeneous disorders with several different etiologies and they are responsible for most cases of short stature. Mutations in different genes have been identified but still many patients did not present mutations in any of the known genes. Chromosomal rearrangements may also be involved in short stature and, among others, deletions of 18q23 defined a critical region for the disorder. No gene was yet identified. We now report a balanced translocation X;18 in a patient presenting a breakpoint in 18q23 that was surprisingly mapped about 500 Kb distal from the short stature critical region. It separated from the flanking SALL3 gene a region enriched in highly conserved non-coding elements (HCNE) that appeared to be regulatory sequences, active as enhancers or silencers during embryonic development. We propose that, during pituitary development, the 18q rearrangement may alter expression of 18q genes or of X chromosome genes that are translocated next to the HCNEs. Alteration of expression of developmentally regulated genes by translocation of HCNEs may represent a common mechanism for disorders associated to isolated chromosomal rearrangements.