Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations - PubMed (original) (raw)

Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations

Barbara Lanthaler et al. Eur J Hum Genet. 2013 Mar.

Abstract

The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Δ7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n=21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P=0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P=0.004. Maternal ABCA1 explains 15.4% (R²) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from Hardy-Weinberg equilibrium (HWE) was observed (P=0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.

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Figures

Figure 1

Figure 1

Box-plot diagram demonstrating the difference between maternal ABCA1 genotypes (Arg1587=11; Arg1587Lys=12; Lys1587=22) with regard to the severity scores of SLOS patients; _P_=0.008 (Mann–Whitney U test).

Figure 2

Figure 2

Schematic representation of the conclusion about transfer of maternal cholesterol to the fetus through placentally expressed ApoE, ABCA1, and ABCG1.

Figure 3

Figure 3

SLOS patient (patient 11 in Table 5).

References

    1. Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. J Pediatr. 1964;64:210–217. -PubMed
    1. Kelley RI, Hennekam RC. The Smith–Lemli–Opitz syndrome. J Med Genet. 2000;37:321–335. -PMC -PubMed
    1. Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, et al. Mutational spectrum in the delta7-sterol reductase gene and genotype–phenotype correlation in 84 patients with Smith–Lemli–Opitz syndrome. Am J Hum Genet. 2000;66:402–412. -PMC -PubMed
    1. Witsch-Baumgartner M, Schwentner I, Gruber M, et al. Age and origin of major Smith–Lemli–Opitz syndrome (SLOS) mutations in European populations. J Med Genet. 2008;45:200–209. -PubMed
    1. Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith–Lemli–Opitz Syndrome. Lancet. 1993;341:1414. -PubMed

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