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

Abstract

Smith-Lemli-Opitz syndrome/RSH (SLOS) is

Malformation syndromes caused by disorders of cholesterol synthesis

“…Further work is necessary to defi ne the environmental, maternal, and genetic factors that contribute to the SLOS phenotype. Many of the common DHCR7 mutations can be traced to specifi c European populations and demonstrate frequency gradients across Europe ( 70 ). IVS8-1G>C appears to have arisen in the British Isles and decreases in frequency as one progresses eastward across Europe.…”

“…IVS8-1G>C and p.W151X are estimated to have arisen approximately 3,000 years ago in northwest and northeast Europe, respectively ( 71 ). The most common missense mutation, p.T93M, is frequently observed in individuals of Mediterranean heritage ( 70,(72)(73)(74) and is estimated to have arisen approximately 6,000 years ago ( 71 ).…”

Abnormal sterols in cholesterol-deficiency diseases cause secretory granule malformation and decreased membrane curvature

“…SLOS is an autosomal-recessive, multiple malformation and/or mental retardation syndrome in which the function of the enzyme, 7-dehydrocholesterol reductase (DHCR7), necessary for the final step of cholesterol biosynthesis, is impaired (Porter, 2000;Tint et al, 1994). SLOS reportedly affects 1:10,000 to 1:40,000 caucasian Americans and is caused by mutations in the gene encoding DHCR7 with the severity of disease dependent on the type of mutation (Witsch-Baumgartner et al, 2001). Another inborn error of cholesterol synthesis is lathosterolosis.…”

A koleszterin-bioszintézis veleszületett zavara: a Smith–Lemli–Opitz-szindróma

“…Mintegy öt mutáció (p.Thr93Met, p.Trp151*, p.Arg404Cys, p.Val326Leu, c.964-1G>C) tehető felelőssé a betegsé-get okozó allélok közel 60%-ért, amelyek közül a c.964-1G>C splicingot befolyásoló mutáció önmagában átla-gosan 30%-ban fordul elő [11]. Más monogénes betegségekhez hasonlóan itt is megfi gyelhető, hogy az egyes populációkban különböző a mutációs spektrum, és az egyes mutációk gyakorisága is a földrajzi elhelyezkedéstől függően eltérő [35].…”