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Uniparental disomy of chromosome 2 resulting in lethal trifunctional protein deficiency due to homozygous ?-subunit mutations

2002; Wiley; Volume: 20; Issue: 6 Linguagem: Inglês

10.1002/humu.10142

1098-1004

Ute Spiekerkoetter, Angela Eeds, Yue Zou, Jonathan L. Haines, Arnold W. Strauss, Marshall Summar,

Genomics and Rare Diseases

The mitochondrial trifunctional protein (TFP) is an enzyme complex of the fatty acid β-oxidation cycle composed of an α- and a β-subunit. The two encoding genes are located in the same region on chromosome 2 (2p23). TFP deficiency due to either α- or β-subunit mutations is characterized by mutational and phenotypic heterogeneity with severe, early-onset, cardiac forms and milder, later-onset, myopathic phenotypes. In two unrelated patients with lethal TFP deficiency, we delineated apparently homozygous α-subunit mutations that were present in heterozygous form in both mothers, but not in either biological father. We performed a microsatellite repeat analysis of both patients and their parents using seven chromosome 2-specific polymorphic DNA markers and four nonchromosome 2 markers. In both patients, two chromosome 2-specific markers demonstrated maternal isodisomy of chromosome 2. The other five chromosome 2-specific markers were noninformative in each patient. Inheritance of alleles from chromosomes 4, 5, and 7 was consistent with paternity. These results explain the apparently anomalous pattern of transmission. Six of our 12 known TFP-deficient patients with α-subunit mutations have disease due to homozygous changes and two of them via the mechanism of uniparental disomy (UPD) (16.7%). For very rare autosomal recessive diseases, UPD may represent a common mechanism. This study emphasizes the need to confirm mutations in parents whenever possible. TFP deficiency is another disorder that has become manifest due to isodisomy of chromosome 2. This information will impact genetic counseling for these families, reducing greatly the 25% risk normally used for recessive disorders. Hum Mutat 20:447–451, 2002. © 2002 Wiley-Liss, Inc.