TY - JOUR T1 - <em>DHCR7</em> nonsense mutations and characterisation of mRNA nonsense mediated decay in Smith-Lemli-Opitz syndrome JF - Journal of Medical Genetics JO - J Med Genet SP - 350 LP - 357 DO - 10.1136/jmg.2004.022749 VL - 42 IS - 4 AU - L S Correa-Cerro AU - C A Wassif AU - J S Waye AU - P A Krakowiak AU - D Cozma AU - N R Dobson AU - S W Levin AU - G Anadiotis AU - R D Steiner AU - M Krajewska-Walasek AU - M J M Nowaczyk AU - F D Porter Y1 - 2005/04/01 UR - http://jmg.bmj.com/content/42/4/350.abstract N2 - Smith-Lemli-Opitz syndrome (SLOS) is the prototypical example of a multiple congenital anomaly mental retardation syndrome due to an inborn error of cholesterol biosynthesis. The SLOS clinical spectrum ranges from a very mild disorder that combines learning and behavioural problems with minor malformations to a severe multiple malformation syndrome that results in prenatal/neonatal death.1,2 In 1998, three groups independently identified mutations of DHCR7 in SLOS patients.3–5DHCR7 was mapped to chromosome 11q12–13 and encodes an NADPH dependent reductase that reduces 7-dehydrocholesterol (7DHC) to cholesterol in the last step of cholesterol biosynthesis. Molecular studies have shown that the carrier frequency for the most common SLOS mutant allele, IVS8-1G→C, is approximately 1% in Caucasian populations.6,7 Due to the deficiency of DHCR7 activity, SLOS patients have elevated 7DHC and typically decreased cholesterol levels. Decreased cholesterol levels have been associated with birth defects due to impaired hedgehog signalling during development.8 One third of mutations underlying human disorders result in premature termination codons (nonsense mutations), which often lead to rapid degradation of the mutant mRNA by the nonsense mediated decay (NMD) pathway.9 Although the molecular mechanisms underlying NMD are not fully understood, NMD can be suppressed by experimental manipulations that impair the efficiency of translation. Aminoglycoside antibiotics, which bind to ribosomes, can induce translational read through of nonsense codons and thus suppress NMD. Restoration of protein function by NMD suppression has been reported in a number of autosomal recessive disorders such as cystic fibrosis10–12 and Hurler syndrome.13,14 Four nonsense mutations have previously been described in SLOS. These are E37X,15 Q149X,16 W151X,3 and Y217X.16 W151X represents about 6.4% of identified mutations in SLOS patients17 and by haplotype analysis appears to be a relatively old DHCR7 mutation that initially arose in … ER -