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Incidence and molecular mechanism of aberrant splicing owing to a G→C splice acceptor site mutation causing Smith-Lemli-Opitz syndrome
  3. G J ROMEIJN*,
  4. R J A WANDERS*,
  1. * Laboratory for Genetic Metabolic Diseases (F0-226), Departments of Clinical Chemistry and Paediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands
  2. Department of Paediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands
  1. Dr Waterham, h.r.waterham{at}

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Editor—Smith-Lemli-Opitz (SLO) syndrome (MIM 270400) is an autosomal recessive disorder characterised by a wide spectrum of developmental abnormalities including craniofacial malformations, growth and mental retardation, and multiple congenital anomalies.1-3 The disorder is caused by deficient activity of 7-dehydrocholesterol reductase (7-DHCR), the enzyme that catalyses the reduction of the C7-C8 (Δ7) double bond of 7-dehydrocholesterol to produce cholesterol.4 5 As a consequence, patients with SLO syndrome have low plasma cholesterol and raised plasma 7-dehydrocholesterol concentrations, thus constituting the biochemical hallmark used to confirm the clinical diagnosis of the syndrome.

Recently, we and others have identified the cDNA coding for human 7-DHCR and confirmed that SLO syndrome is caused by mutations in the corresponding 7-DHCR gene.6-8 So far, 19 different disease causing mutations have been reported, which were identified after analysis of only 33 patient alleles. In our previous report, we described an aberrantly spliced mutant 7-DHCR cDNA with an insertion of 134 bp which we identified in two of three Dutch patients analysed with SLO syndrome, one of whom was a homozygote and the other a compound heterozygote.6 Upon translation, this insertion not only introduces additional amino acids but also causes a frameshift, which leads to an inactive, truncated protein with a changed C-terminus.6 Since the same insertion was also reported by two other groups,7 8 and since the affected patients were not related to one another, this finding suggested that the insertion is the result of a frequently occurring mutation. To evaluate this, we analysed 17 additional patients with SLO syndrome for the occurrence of the 134 bp insertion using allele specific RT-PCR. Furthermore, we studied the underlying mechanism that gives rise to the aberrant splicing, which results in the 134 bp insertion at the cDNA level.

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