Severe primary pulmonary hypoplasia ("acinar dysplasia") in sibs: a genetically determined mesodermal defect?

Secondly, other, as yet unidentified, mutations in the mt genome of the patients could have a modulatory effect on the phenotypic expression of the thymine deletion. PCRSSCP analysis of all other tRNA genes did not show additional mtDNA variations, but the complete sequence of the mt genome was not determined. Therefore, the presence of an additional heteroplasmic mtDNA mutation cannot be excluded. Thirdly, the mt genome is known to be highly polymorphic. Therefore, the deletion could be classified as a very uncommon genetic polymorphism, and its presence in the two families suffering from mt disorders is no more than a striking coincidence. We screened, along with the two families, more than 70 people (both patients and controls) for mutations in the same DNA fragment. Five different nucleotide substitutions, at positions 15904 C to T, 15907 A to G, 15924 A to G, 15928 G to A in tRNA'tr (all previously reported), and 16017 T to C in tRNAP-, were identified.5 6 All sequence variations were homoplasmic and observed both in patients and control mtDNA. The tRNAthr gene also harbours several nucleotide alterations responsible for mt encephalomyopathies: a G to A transition at nucleotide 15915, an A to G point mutation at nucleotide 15923, and a G to A mutation at bp 15927.5 This particular DNA fragment seems to represent a "hot spot" for DNA variations in the mt genome. This report illustrates the difficulties in diagnosing mt disorders. More pedigrees with this deletion mutation will need to be characterised to understand the real significance of this DNA aberration. In addition, micro-rearrangements involving tRNA genes should be considered as possible causes for oxidative phosphorylation diseases, even if they are homoplasmic in both patients and unaffected relatives.