RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis

Article Abstract:

Smith-Lemli-Opitz syndrome (SLOS), also called RSH syndrome, is reviewed in relation to metabolic morphogenesis and the mutations involved. It is an autosomal recessive, multiple anomaly syndrome that is characterized by genital malformation in males, polydactyly, and craniofacial anomalies including cleft palate. Patients with this syndrome have an increased blood levels of 7-dehydrocholesterol (7DHC), increased by as much as a factor of 2,000. The molecule is the immediate precursor of cholesterol in the Kandutch-Russell cholesterol biosynthesis pathway. The clinical phenotype has been expanded and some near-normal children are included as well as some very defective fetuses that die before birth. Patients' lives are dramatically improved when the cholesterol-deficiency syndrome is treated. Other biochemically undiagnosed malformation syndromes will be investigated for disorders of cholesterol biosynthesis but mutations that bring many malformations have been those of of homeobox genes and other transcription regulators and signaling systems.

Birth defects, Cellular signal transduction, Biochemical genetics, Sterols

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Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxylbutyric aciduria)

Article Abstract:

Two exon-skipping mutations appear to be the molecular basis of succinic semialdehyde dehydrogenase (SSADH) deficiency or 4-hydroxylbutyric aciduria. SSADH is a rare metabolic disorder of 4-aminobutyric acid degradation identified in about 150 patients. The found mutations alter highly conserved sequences at intron-exon boundaries and keep the RNA -splicing mechanism from recognizing the normal splice junction as it should. Each family segregated a mutation in a different splice site. Exon skipping was the result with a frameshift and premature termination in one case. In the other there was in-frame deletion in the resulting protein. Family members were heterozygotes for the splicing abnormality, evidence of autosomal recessive inheritance. Two point mutation in the SSADH genes derived from four patients were identified.

Italy, Netherlands, Succinic acid

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Missense mutations in disease genes: a Bayesian approach to evaluate causality

Article Abstract:

A Bayesian approach to uses genetic information on affected relatives in families ascertained through known missense mutation carriers has been proposed and demonstrated in two cancer data sets. The problem of interpreting disease gene missense mutations is more important as time goes on. The point mutations result in alteration of a single amino acid of the protein products. It is often not clear whether there is enough change to cause disease.

Methods, Usage, Bayesian statistical decision theory, Bayesian analysis, Cancer, Cancer genetics, Chromosome mapping, Medical statistics

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