Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy. Patients with WS frequently develop deafness, diabetes insipidus, renal tract abnormalities, and diverse psychiatric illnesses, among others. A gene responsible for WS was identified on 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein present in a wide spectrum of tissues. A new locus for WS has been located on 4q22-24, providing evidence for the genetic heterogeneity of this syndrome. Six Spanish families with a total of seven WS patients were screened for mutations in the WFS1-coding region by direct sequencing. We found three previously undescribed mutations c.873C > A, c.1949_50delAT, and c.2206G > C, as well as the duplication c.409_424dup16, formerly published as 425ins16. Several groups had detected deletions in the mitochondrial DNA (mtDNA) of WS patients. For this reason, we also studied the presence of mtDNA rearrangements as well as Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and A1555G point mutations in the WS families. No mtDNA abnormalities were detected.

Alleles↗

PubMed2003

[Cystinuria].

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Amino Acid Transport Systems↗

PubMed2001

Mitochondrial involvement in antiretroviral therapy-related lipodystrophy.

OBJECTIVES: The management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4(+) cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug. DESIGN: Seven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder. METHODS: Histological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria. RESULTS: Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. CONCLUSIONS: The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

Adult↗

PubMed2001

[Analysis of mutations A3243G, C3256T and mitochondrial deletions in 41 diabetic patients].

BACKGROUND: Mutations or deletions of mitochondrial DNA (mtDNA) define a new diabetes subtype. PATIENTS AND METHOD: The A3243G and C3256T mutations and mtDNA deletions were studied in 41 diabetic patients with maternally inherited diabetes mellitus or deafness. RESULTS: The A3243G mutation was found in one out of forty-one diabetic patients (2.4%). Neither the C3256T mutation nor mtDNA deletions were detected. CONCLUSIONS: The search of A3243G mutation has to be considered in a diabetic patient with deafness and/or maternal history of diabetes.

Adult↗

PubMed2001

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

Amino Acid Sequence↗