Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by a disorder in cholesterol metabolism. SLOS is caused by mutations in the DHCR7 gene which encodes 7-dehydr...Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by a disorder in cholesterol metabolism. SLOS is caused by mutations in the DHCR7 gene which encodes 7-dehydrocholesterol reductase, an enzyme that catalyses the final step in cholesterol biosynthesis. We have previously established the clinical and photobiological features of the photosensitivity that is frequently a feature of SLOS. Objectives: In this study, we have performed mutational analysis of the DHCR7 gene in individuals from five fa milies with SLOS. In each family, one member was affected by severe photosensiti vity as a manifestation of SLOS. Methods: Fifteen samples (including family cont rols)-were screened using polymerase chain reaction amplification and direct au tomated sequencing. Results: Six different DHCR7 mutations were identified of wh ich five were single point mutations that causedmissense amino acid substitution s (P51H, T93M, L99P, E448K and R450L). The other was a splice site mutation (G →C in splice acceptor site) affecting the intron 8-exon 9 splice junction (IVS 8-1G→C). This splice sitemutation and four of the five missense mutations have been previously published as causal in SLOS but the P51H is a novel mutation wh ich has not previously been reported. Conclusions: This is the first study in wh ich DHCR7 gene mutational analysis has been performed on SLOS subjects with seve re photosensitivity and indicates that no single mutation is responsible for the photosensitivity which characterizes this disorder.展开更多
文摘Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by a disorder in cholesterol metabolism. SLOS is caused by mutations in the DHCR7 gene which encodes 7-dehydrocholesterol reductase, an enzyme that catalyses the final step in cholesterol biosynthesis. We have previously established the clinical and photobiological features of the photosensitivity that is frequently a feature of SLOS. Objectives: In this study, we have performed mutational analysis of the DHCR7 gene in individuals from five fa milies with SLOS. In each family, one member was affected by severe photosensiti vity as a manifestation of SLOS. Methods: Fifteen samples (including family cont rols)-were screened using polymerase chain reaction amplification and direct au tomated sequencing. Results: Six different DHCR7 mutations were identified of wh ich five were single point mutations that causedmissense amino acid substitution s (P51H, T93M, L99P, E448K and R450L). The other was a splice site mutation (G →C in splice acceptor site) affecting the intron 8-exon 9 splice junction (IVS 8-1G→C). This splice sitemutation and four of the five missense mutations have been previously published as causal in SLOS but the P51H is a novel mutation wh ich has not previously been reported. Conclusions: This is the first study in wh ich DHCR7 gene mutational analysis has been performed on SLOS subjects with seve re photosensitivity and indicates that no single mutation is responsible for the photosensitivity which characterizes this disorder.
