LETTER TO JMG

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

L S Correa-Cerro¹, C A Wassif¹, J S Waye², P A Krakowiak^1,*, D Cozma¹, N R Dobson³, S W Levin⁴, G Anadiotis⁵, R D Steiner⁶, M Krajewska-Walasek⁷, M J M Nowaczyk², F D Porter¹

¹ Unit 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 Department of Pathology and Molecular Medicine and Pediatrics, McMaster University, Hamilton, ON, Canada
³ Department of Pediatrics, National Naval Medical Center, Bethesda, MD, USA
⁴ Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC, USA
⁵ Legacy Children’s Hospital, Pediatric Development and Rehabilitation, Portland, OR, USA
⁶ Departments of Pediatrics and Molecular and Medical Genetics, Child Development Rehabilitation Center, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR, USA
⁷ Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland

Correspondence to:
Correspondence to:
Forbes D Porter
Heritable Disorders Branch, NICHD, NIH, DHHS, Bld. 10, Rm. 9S241, 10 Center Dr., Bethesda, MD 20892, USA; fdporter@mail.nih.gov

Received 12 May 2004
Revised version received 16 June 2004

Abbreviations: 7DHC, 7-dehydrocholesterol; DMEM, Dulbecco’s Modified Eagle’s Medium; LPDS, lipoprotein deficient serum; NMD, nonsense mediated decay; SLOS, Smith-Lemli-Opitz syndrome

Keywords: 7-dehydrocholesterol reductase; DHCR7; mRNA nonsense mediated decay; Smith-Lemli-Opitz syndrome; suppression of nonsense mediated decay

The first 150 words of the full text of this article appear below.

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, IVS8-1GC, 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 . . . [Full text of this article]

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