Mutational Spectrum in the Δ7-Sterol Reductase Gene and Genotype-Phenotype Correlation in 84 Patients with Smith-Lemli-Opitz Syndrome

Abstract

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation syndrome, ranges in clinical severity from mild dysmorphism and moderate mental retardation to severe congenital malformation and intrauterine lethality. Mutations in the gene for Delta7-sterol reductase (DHCR7), which catalyzes the final step in cholesterol biosynthesis in the endoplasmic reticulum (ER), cause SLOS. We have determined, in 84 patients with clinically and biochemically characterized SLOS (detection rate 96%), the mutational spectrum in the DHCR7 gene. Forty different SLOS mutations, some frequent, were identified. On the basis of mutation type and expression studies in the HEK293-derived cell line tsA-201, we grouped mutations into four classes: nonsense and splice-site mutations resulting in putative null alleles, missense mutations in the transmembrane domains (TM), mutations in the 4th cytoplasmic loop (4L), and mutations in the C-terminal ER domain (CT). All but one of the tested missense mutations reduced protein stability. Concentrations of the cholesterol precursor 7-dehydrocholesterol and clinical severity scores correlated with mutation classes. The mildest clinical phenotypes were associated with TM and CT mutations, and the most severe types were associated with 0 and 4L mutations. Most homozygotes for null alleles had severe SLOS; one patient had a moderate phenotype. Homozygosity for 0 mutations in DHCR7 appears compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used.

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

“…9 Recently the gene coding for DHCR7 has been cloned 14 and mutations in the gene were identified in all patients with biochemically confirmed SLOS. [15][16][17][18][19][20] The mutational spectrum in the DHCR7 gene from a large group of patients with SLOS has been determined and a genotype-phenotype correlation has been established. 18 Altogether over 40 DHCR7 mutations have been described in SLOS patients some of which were frequent.…”

Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse

“…Although SLOS was initially classified clinically into two groups, SLO type I and SLO type II, based upon clinical criteria and severity, current observations suggest that these are but two ends of a continuous spectrum of severity. In previous investigations, we and others have shown that severity of SLOS disease correlates with plasma cholesterol levels, but that this does not account for all of the observed variations in severity [5,10]. Additionally, it is not uncommon to note dissimilar phenotypes in affected siblings, suggesting that factors other than mutations in DHCR7 affect phenotype.…”

“…Genotype-phenotype correlations show that a wide-spectrum of mutations in the DHCR7 gene can cause SLOS, but these mutations may account for only an estimated 50% of the severity of the disease [10,30]. Within a single family, the severity scores of two affected siblings can be different [10].…”

“…As a result, in SLOS patients, there is a deficiency of cholesterol in tissues, with simultaneous accumulation of precursor sterols, mainly 7-and 8-dehydrocholesterols. A wide spectrum of mutations in DHCR7 have now been reported to cause SLOS, with three mutations accounting for more than 70% of the mutant alleles [2][3][4][5]10]. Although SLOS was initially classified clinically into two groups, SLO type I and SLO type II, based upon clinical criteria and severity, current observations suggest that these are but two ends of a continuous spectrum of severity.…”

“…The Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive disorder of sterol metabolism characterized by the loss of enzymatic activity of 3ß-hydroxysterol Δ7 reductase (Dhcr7) [1][2][3][4][5][6][7]. This leads to a classical dysmorphism/malformation syndrome, with severity ranging from early embryonic loss to variable survival after birth.…”