Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of Δ7-sterol reductase in Italy and report of three novel mutations

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation and multiple congenital anomalies. SLOS is caused by mutations of the human ∆7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have been described. Among these, mutations impairing the activity of the C-terminus appear to be the most severe. Here we report the mutational analysis of the DHCR7 gene in nine Italian SLOS patients. The T93M mutation, previously reported in one patient, results the most frequent one (7/18 alleles) in our survey. Furthermore, we identified three novel mutations, two missense mutations (N407Y and E448K), and a 33 bp deletion spanning part of exon 5 and the donor splice site of intron 5.

Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations

“…This mutation is obviously rare in South and East Europe. It was not observed among 18 SLOS alleles from southern Italy 24 and is rare in Poland (see Table 1). Its frequency increased towards the northwest.…”

“…Twenty-six of these have been previously identified by us 15,18 and others. 16,17,19,[24][25][26] Six of the mutations have not been described before (T154R, M270V, G309S, R443H, I178N, R242H). No mutation was found on four out of 118 SLOS chromosomes from four patients (96.6% mutation-detection rate).…”

“…Hence the distribution pattern of DHCR7 mutations in Europe as it starts to emerge from this study might be a reflection of ancient and modern migrations in Europe. In a recent study De Brasi et al 24 reported that T93M is the most frequent DHCR7 mutation in Italian SLOS patients. Thus the pattern of SLOS mutations in Caucasians may be more complex than indicated by the present data.…”

“…The third most frequent mutation (0.068) in the British T93M was recently identified as the most frequent mutation among Italian SLOS patients. 24 All other British SLOS mutations were rare and represented by only one or two alleles.…”

Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

“…The net production of cholesterol is catalyzed by a delta-7-sterol reductase (DHCR7, 7-dehydrocholesterol reductase), a NADPH dependent oxidoreductase located at the endoplasmic reticulum (ER). As a cholesterol-synthesising enzyme, interest has grown in DHCR7 since its discovery as the product of the gene mutated in the Smith-LemliOpitz syndrome (SLOS) Wassif et al, 1998;De Brasi et al, 1999), which was first identified in 1964 as a recessive malformation/mental retardation syndrome (Nowaczyk and Waye, 2001;Prasad et al, 2002;Jira et al, 2003;Nowaczyk et al, 2004). Until now, isolation of DHCR7 cDNA has been reported for several species including humans, mice Moebius et al, 1998), rats (Bae et al, 1999), and Arabidopsis (Lecain et al, 1996).…”