TY - JOUR
T1 - Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: Evidence for different origins of common mutations
AU - Witsch-Baumgartner, M.
AU - Ciara, E.
AU - Löffler, J.
AU - Menzel, H. J.
AU - Seedorf, U.
AU - Burn, J.
AU - Gillessen-Kaesbach, G.
AU - Hoffmann, G. F.
AU - Fitzky, B. U.
AU - Mundy, H.
AU - Clayton, P.
AU - Kelley, R. I.
AU - Krajewska-Walasek, M.
AU - Utermann, G.
N1 - Funding Information:
We thank Drs P Bittigau, G Krüger. P Meinecke, H Thiele, B Utermann, U Wendel, M and N Blandfort, H Zierler, and H Rehder for samples and for clinical data on their patients with SLOS. The skillful technical assistance of Ramona Berberich is gratefully acknowledged. BU Fitzky was supported by the Austrian Science Fund grant P 11636 to H Glossmann. This work was supported by the Austrian Science Fund grant P 12792-GEN to GU. MW-B and EC contributed equally to this work.
PY - 2001
Y1 - 2001
N2 - Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for △7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions.
AB - Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for △7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions.
UR - http://www.scopus.com/inward/record.url?scp=0035146784&partnerID=8YFLogxK
U2 - 10.1038/sj.ejhg.5200579
DO - 10.1038/sj.ejhg.5200579
M3 - Journal articles
C2 - 11175299
AN - SCOPUS:0035146784
SN - 1018-4813
VL - 9
SP - 45
EP - 50
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -