Transition m.3308T>C in the ND1 gene is associated with left ventricular hypertrabeculation/noncompaction.

Though left ventricular hypertrabeculation/noncompaction (LVNC) is frequently associated with mitochondrial DNA (mtDNA) mutations, it has not been reported in association with the transition m.3308T>C of the NADH dehydrogenase subunit 1 (ND1) gene. The index patient is a 16-year-old Tunisian female who was investigated for a systolic murmur and cardiomegaly. Echocardiography revealed tricuspid insufficiency, moderate left ventricular dilatation, Ebstein's anomaly, a superior caval vein draining into the coronary sinus and, surprisingly, LVNC of the apex and the lateral wall. LVNC was absent in all other cardiologically investigated siblings. RNA and mtDNA sequence analysis revealed the known homoplasmic mutation m.3308T>C resulting in the replacement of the first amino acid methionine by threonine in the ND1 subunit of respiratory chain complex I. The m.3308T>C mutation was also present in the patient's mother and several other family members but absent in 350 controls. Additionally, the index patient carried the polymorphisms m.8248A>G in the COX2 gene and m.8468C>T in the ATP8 gene. It is concluded that LVNC may be associated with the known homoplasmic m.3308T>C mutation in the ND1 gene. However, the pathogenetic role of this mutation in the development of LVNC remains elusive.

Screening of the DFNB3 locus: identification of three novel mutations of MYO15A associated with hearing loss and further suggestion for two distinctive genes on this locus.

Recessive mutations of MYO15A are associated with nonsyndromic hearing loss (HL) in humans (DFNB3) and in the shaker-2 mouse. Human MYO15A has 66 exons and encodes unconventional myosin XVA. Analysis of 77 Tunisian consanguineous families segregating recessive deafness revealed evidence of linkage to microsatellite markers for DFNB3 in four families. In two families, sequencing of MYO15A led to the identification of two novel homozygous mutations: a nonsense (c.4998C>A (p.C1666X) in exon 17 and a splice site mutation in intron 54 (c.9229 + 1G>A). A novel mutation of unknown significance, c.7395 + 3G>C, was identified in the third family, and no mutation was found in the fourth family. In conclusion, we discovered three novel mutations of MYO15A, and our data suggest the possibility that there are two distinct genes at the DFNB3 locus.

A novel mitochondrial DNA tRNAIle (m.4322dupC) mutation associated with idiopathic dilated cardiomyopathy.

We identified a novel heteroplasmic mitochondrial DNA (mtDNA) (m.4322dupC) mutation in tRNA gene associated with isolated dilated cardiomyopathy (DCM) as maternal trait. Mutation screening techniques and automated DNA sequencing were performed to identify mtDNA mutations and to assess heteroplasmy in family's proband and healthy control subjects. All family members tested had heteroplasmic mtDNA m.4322dupC mutation. We also screened 350 normal controls for this mutation and found no evidence of heteroplasmy. The m.4322dupC mutation was found in the skeletal tissue from the proband that exhibited slightly reduced deficiency of mitochondrial respiratory chain enzymes (complex III). The present study reports the novel m.4322dupC mutation in tRNA gene, which is possibly associated to the disease, to isolated DCM. It was localized in a hot-spot region for mutations and is possibly pathogenic because of a cosegregation with the matrilineal transmission of DCM.

Clinical and genetic analysis of two Tunisian otosclerosis families.

Otosclerosis is caused by an abnormal bone homeostasis of the otic capsule resulting in a conductive hearing loss when the free motion of the stapes is compromised. An additional sensorineural hearing loss arises in some patients, most likely due to otosclerotic foci that invade the cochlear endosteum. Otosclerosis is a very common hearing impairment among Caucasians with a prevalence of about 0.3-0.4% among white adults. In the majority of cases, otosclerosis can be considered as a complex disease, caused by both genetic as environmental factors, but autosomal dominant forms of otosclerosis exist. However, families large enough for genetic analysis are very rare and often show reduced penetrance. To date five loci have been reported, but none of the genes have been cloned yet. In this study, we analyzed two new autosomal dominant otosclerosis families from Tunisia, and genotyped them with microsatellite markers for the known loci, the collagen genes COL1A1 and COL1A2, and NOG gene. In the family LK, linkage to all known loci was excluded. However, the family LS shows suggestive linkage to the OTSC3 region on chromosome 6p21.3-p22.3. This result points out that, besides the five reported loci, there must be at least one additional locus for autosomal dominant otosclerosis.