Identification of 14 novel mutations inDHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of theDHCR7 mutational spectra in Spain and Italy

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is a phenotypically variable metabolic malformation and mental retardation syndrome for which more than 80 mutations in the DHCR7 disease-causing gene have been described. The DHCR7 mutational spectra differ significantly in different areas of Europe, and several common putative founder mutations account for a substantial fraction of all mutations in some ethnic groups. Here we have analysed 47 SLOS patients and describe 14 newly identified mutations in 18 SLOS patients of Ashkenazi Jewish, Austrian, British, German, Italian, Irish, Polish, Portuguese, and Spanish origins. Half of the new mutations are in the transmembrane domains of the protein. In addition, there were two null mutations, one mutation in the 4th cytoplasmic loop, two mutations in the first and last codons, and three mutations in other regions such as the second cytoplasmic loop and the first endoplasmic loop. The analysis included 20 Spanish and 12 Italian SLOS patients and revealed very different mutation spectra in these patients compared to previously described patients from Czechoslovakia, Germany, Poland, and the UK and implicated p.Thr93Met on the J haplotype as the most frequent Mediterranean founder mutation.

R352Q mutation of the DHCR7 gene is common among Japanese Smith–Lemli–Opitz syndrome patients

“…We have identified five mutations in seven SLOS patients. The R242H, R352Q, and S192F mutations have been reported in non-Japanese populations (Krakowiak et al 2000;Witsch-Baumgartner et al 2000, 2005, whereas G303R and X476Q were previously undescribed mutations. The S192F, R242H, G303R and R352Q mutations are located within the fourth, the fifth, the seventh, and the eighth transmembrane domains, all of which represent a highly conserved sterol-sensing domain (Bae et al 1999;Krakowiak et al 2000).…”

“…More than 80 different mutations have been reported in SLOS patients from the USA and Europe Witsch-Baumgartner et al 2005). Three mutations account for over 50% of those observed: IVS8-1G fi C, T93M, and V326L (Yu et al 2000a).…”

“…The R242H and R352Q both likely affect DHCR7 protein stability, since functional analysis, by expression of similar mutations (R242C and R352W) in a human cell line, demonstrated that the mutations resulted in reduced protein expression (<3%) Witsch-Baumgartner et al 2000). The S192F mutation has recently been reported in a European patient with mild severity (Witsch-Baumgartner et al 2005). The G303R newly identified in two patients 99010 and 04004 is likely pathogenic because it was heterozygous in the patients and their parents, but absent in 184 control chromosomes, and the 303rd residue is conserved in the orthologues of cattle, mouse, rat, and zebrafish.…”

Clinical utility gene card for: Smith-Lemli-Opitz Syndrome [SLOS]

“…Characterisation of the mutational spectrum of the DHCR7 gene was possible after studying 4100 SLOS patients (Witsch-Baumgartner M et al 4,5 Correa-Cerro et al 6 ). Until now 4100 different mutations: nonsense (eg, p.Trp151*), deletions (eg, c.720-735del and c.385-412IVS5 þ 1-5del, HGVS: c.385_412 þ 5del), splice site mutations (eg, c.964-1G4C) and missense mutations have been described.…”

Spectrum of DHCR7 mutations in Slovak patients with Smith-Lemli-Opitz syndrome and detection of common mutations by PCR-based assays

“…Missense mutations are the most common (Cardoso et al 2005;Correa-Cerro and Porter 2005;Witsch-Baumgartner et al 2005;Yu and Patel 2005) and have been classified according to the predicted domains of DHCR7: transmembrane domains, the 4 th cytoplasmic loop, C-terminus (Witsch-Baumgartner et al 2001a).…”