The novel tRNAMet A4435G mutation has a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.

No abstract

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity ofAPC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on Sq including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers.

Purpose-To investigate the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families. Design-EightHan Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.Participants-One hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment.Methods-All subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA).Main Outcome Measures-The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. Mitochondrial DNA analysis included the polymerase chain reaction amplification of the entire mtDNA and subsequent sequence determination.Results-Eight families exhibited extremely low penetrance of visual impairment, with the average of 13%. In particular, 14 (12 males and 2 females) of 119 matrilineal relatives in these families exhibited the variable severity and age at onset in visual dysfunction. The average age of onset of vision loss was 17 years. Molecular analysis of mtDNA identified the homoplasimic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M8a2, D4g2, B4a1c, B5b, N9a1, D4b2b, C, and M7b1. However, there was an absence of secondary LHONassociated mtDNA mutations in these 8 Chinese families. Conclusions-The extremely low penetrance of vision loss in these 8 Chinese pedigrees strongly indicates that the G11778A mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G11778A mutation in those Chinese families with very low penentrace of vision loss. However, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the G11778A mutation in these Chinese families.Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder leading to the rapid, painless, and bilateral loss of central vision. [1][2][3][4] Mutations in mitochondrial DNA (mtDNA) are the molecular bases for this disorder. [5][6][7] Of these, the ND1 G3460A, ND4 G11778A, and ND6 T14484C mutations, which involve genes encoding the subunits of respiratory chain complex I, account for more than 50% of LHON pedigrees worldwide. [8][9][10] Those LHON-associated mtDNA mutations, unlike other pathogenic mtDNA mutations such as the Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)-associated tRNA Leu(UUR) A3243G mutation present in heteroplasmy (mixture of mutated and wild-type molecules), 11 often occur nearly homoplasmy or homoplasmy. Such mtDNA mutations as the G11778A mutation often exhibit incomplete penetrance because some individuals carrying the mutations have normal vision. 4,8,10,12 In addition, matrilineal ...