J Med Genet 42:350-357 doi:10.1136/jmg.2004.022749
  • Letters to JMG

DHCR7 nonsense mutations and characterisation of mRNA nonsense mediated decay in Smith-Lemli-Opitz syndrome

  1. L S Correa-Cerro1,
  2. C A Wassif1,
  3. J S Waye2,
  4. P A Krakowiak1,*,
  5. D Cozma1,
  6. N R Dobson3,
  7. S W Levin4,
  8. G Anadiotis5,
  9. R D Steiner6,
  10. M Krajewska-Walasek7,
  11. M J M Nowaczyk2,
  12. F D Porter1
  1. 1Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
  2. 2Department of Pathology and Molecular Medicine and Pediatrics, McMaster University, Hamilton, ON, Canada
  3. 3Department of Pediatrics, National Naval Medical Center, Bethesda, MD, USA
  4. 4Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC, USA
  5. 5Legacy Children’s Hospital, Pediatric Development and Rehabilitation, Portland, OR, USA
  6. 6Departments of Pediatrics and Molecular and Medical Genetics, Child Development Rehabilitation Center, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR, USA
  7. 7Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland
  1. Correspondence to:
 Forbes D Porter
 Heritable Disorders Branch, NICHD, NIH, DHHS, Bld. 10, Rm. 9S241, 10 Center Dr., Bethesda, MD 20892, USA;
  • Received 12 May 2004
  • Revised 16 June 2004

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 …