A de novo large deletion of 2.8 kB produced in ABCD1 gene causing Adrenoleukodystrophy disease

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma, adrenal, testicular and nervous tissues. In the present study, our objective is to conduct a clinical, molecular and genetic study of a Tunisian patient with X-linked adrenoleukodystrophy. The clinical diagnosis was based on clinical symptoms, biochemical levels, typical scanner pattern and molecular biology. Whereas, the molecular analysis was based on PCR, long range PCR and sequencing. The molecular analysis by long range PCR and direct sequencing of the ABCD1 gene showed the presence of a de novo 2794 bp deletion covering the whole of exon 2. Using bioinformatics tools, we demonstrate that the large deletion is located in a region rich of Alu sequences. Furthermore, we suggest that the AluJb sequence can be the cause of the large deletion of intron 1, exon 2 and intron 2 and creation of premature stop codon within exon 3. The present report, however, is the first report in which we demonstrate the breakpoints and the size of a large deletion in an X-ALD Tunisian patient.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Severe Wolfram Syndrome Caused by a Novel Frameshift Mutation in WFS1 Gene : Effect on the WFS1/CaM Interaction and Phenotype-Genotype Correlation

Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS), a rare and autosomal recessive disorder defined by early onset of diabetes mellitus and progressive optic and hearing impairment. Only few data are available concerning the association between clinical and molecular aspects of the WFS. We present a consanguineous family with a patient presenting an early onset of WFS and severe manifestations. Sequencing of WFS1 gene was performed for all the family members to search for responsible mutation and bioinformatics tools were conducted to predict its effect on structure and function of the protein. We have detected a novel frameshift mutation in the proband at homozygous state and at the heterozygous state in the parents who have no WFS manifestations. In silico analysis predicted the pathogenicity of the mutation and could lead to a complete loss of its function. Thus, 3D modeling showed that the mutation abolishes the interaction of the CaM binding region to the N-terminal of WFS1 and then impairs the WFS1-CaM complex formation. Genotype-phenotype correlation study shows that the novel mutation predisposes to early onset of diabetes and severe symptoms observed in the proband. We also report the effect of the frameshift mutation on the CaM-WFS1 impaired binding, and we discuss its possible consequence in pancreatic β-cells dysfunction and its role in the early onset of diabetes. In conclusion, the combination of impaired functions of WFS1 including unproper interaction of the CaM, Ca2+ uptake, mitochondrial dysfunction, and apoptosis under the ER stress could be involved in the severe phenotype and early onset of WFS of our patient

Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion

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