237: Mitochondrial DNA mutations associated with neonatal hemochromatosis.

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Anne ... and others;

Just found this ... perhaps it will be helpful if you haven't seen it

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http://www.faseb.org/genetics/ashg99/f237.htm

Program Nr: 237

Mitochondrial DNA mutations associated with neonatal hemochromatosis. M.D. Brown1, D. Chitayat2, J. 1, S. Hosseini1, J. Litten1, R. Babul-Hirji2, D.C. Wallace1. 1) Center for Molecular Medicine, Emory University School of Medicine, Atlanta, GA; 2) Dept. of Genetics, The Hospital for Sick Children, Toronto, ON, Canada.

Neonatal hemochromatosis (NH) is a heterogeneous disorder of prenatal onset which is characterized by systemic iron accumulation, ultimately leading to severe hepatic disease. Although NH typically manifests as sporadic cases, there are several reports in the literature of mothers who had NH infants by different partners. Both of theses familial presentations are common in disorders due to mitochondrial DNA (mtDNA) mutations. Also, neonatal/early onset hepatic failure has been associated with oxidative phosphorylation defects. To test the hypothesis that mtDNA mutations can contribute to NH, we performed mtDNA sequence analysis on two families in which siblings (Family 1) or half-siblings (with a common mother; Family 2) exhibited NH. Family 1 contained a novel, homoplasmic, G to A missense mutation at nucleotide position (np) 13711 which changed an alanine to a threonine in the ND5 subunit of complex I. Family 2 harbored a T to C transition at np 9957 which converted a highly conserved phenylalanine to a leucine in the COIII subunit of complex IV. To determine if the 9957 mutation was heteroplasmic, we cloned the mtDNA from the mother of Family 2 and found low levels (roughly 2%) of wild-type mtDNA. Control cloning experiments suggested that this heteroplasmy was not due to PCR-generated artifact during the cloning process. Neither the np 13711 nor the np 9957 mutations have been found in control mtDNAs. The np 9957 mutation has, however, been reported to be heteroplasmic in a patient with early onset, progressive, mitochondrial encephalomyopathy. Thus, the np 9957 mutation has only been found in the heteroplasmic state and only in association with disease. This suggests that at least this mutation may contribute to the heterogeneous etiology of NH, potentially providing the first direct linkage between a mtDNA mutation and liver disease.