Molecular genetic studies of three autosomal recessive disorders : Sjögren-Larsson syndrome, glutathione synthetase deficiency and congenital ichthyosis

Detta är en avhandling från Uppsala : Acta Universitatis Upsaliensis

Sammanfattning: Investigations at the DNA level were performed in order to characterise the molecular basis forthree genetic disorders:Sjögren-Larsson syndrome (SLS) is characterised by congenital ichthyosis and severeneurological symptoms. Linkage analysis and allelic association of 24 Swedish families affectedby SLS showed linkage between the disease and the marker D17S805 on chromosome 17. The distance between the marker D17S805 and the SLS gene was calculated to 0.6 cM or approximately 600 kb.Glutathione synthetase (GS) deficiency may be characterised by 5-oxoprolinuria,metabolic acidosis, haemolytic anaemia and sometimes central nervous system damage. Ninepatients with severe GS deficiency were sequenced for mutations in the GS gene onchromosome 20. Thirteen different missense mutations were found, of which 10 are novel.Expression studies of four engineered mutations confirmed the pathogenicity.Congenital ichthyosis (IC) is a heterogeneous group of recessive skin disorders includinglamellar ichthyosis (LI) & congenital ichthyosiform erythroderma (CIE). LI and CIE patientsfrom 43 Norwegian families were investigated for mutations in the TGM1 gene. A single splicesite mutation (2526A→G) in intron 5 was found on 80% of LI and CIE alleles of IC type I andII. Prenatal diagnosis based on chromosome 14q11 haplotyping were performed in twoNorwegian LI/CIE families and revealed one disease associated and one normal haplotype in thefoetuses of both families. Subsequent mutation analysis confirmed the results. We analysed LIand CIE patients from 28 Swedish families for mutations in the TGM1 gene. A missensemutation resulting in Ser358Arg and the splice site mutation 2526A→G were found on 52% ofalleles. Thirteen additional mutations were found of which nine are novel. Three individualsaffected by non-lamellar, non-erythrodermic ichthyosis were characterised for mutations in theTGM1 gene. Three mutations were found of which two are novel. The corresponding aminoacid substitutions result in a relatively mild IC phenotype.

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