RESUMO
Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.
Assuntos
Densidade Óssea , Proteínas Morfogenéticas Ósseas , Marcadores Genéticos , Osteocondrodisplasias/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 17 , Análise Mutacional de DNA , DNA Complementar , Ligação Genética , Humanos , Dados de Sequência Molecular , Osteocondrodisplasias/genética , Conformação Proteica , Proteínas/genética , RNA Mensageiro/genética , Homologia de Sequência de AminoácidosRESUMO
We describe 3 patients with a new malformation syndrome in 2 sibships in a large kindred from Bahia, Brazil. The parents in both sibships are consanguineous. The syndrome is characterized by malformations of the face, ears, hands and feet, plus mixed deafness and pseudopapilledema. Fifty-four relatives were examined clinically and scored by the number of anomalies. A control sample of 54 individuals was equally examined. The distribution of the number of anomalies per individual (score) is bimodal in the relatives of the patients but unimodal in the control individuals. Detection of heterozygotes was based on the score distribution.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva/genética , Anormalidades Múltiplas/patologia , Adulto , Criança , Consanguinidade , Dermatoglifia , Feminino , Genes Recessivos , Triagem de Portadores Genéticos , Perda Auditiva Condutiva/genética , Perda Auditiva Neurossensorial/genética , Heterozigoto , Humanos , Masculino , LinhagemRESUMO
A recent longitudinal study in children with cystic fibrosis (CF) challenged the common idea that CF is causing short stature. The data, however, showed clearly that short stature cannot be explained by CF alone after the first year of life. We report on a girl suffering from CF and short stature in whom DNA analysis using polymerase chain reaction and Southern blot techniques of the human growth hormone (hGH) gene cluster revealed a 6.7-kb gene deletion encompassing the hGH-1 gene. Anti-hGH antibodies of polyclonal origin developed, leading to a growth arrest after only 2 months of hGH replacement. In addition, a family study was performed, and the haplotypes of the CF gene and hGH gene cluster were analyzed.
