GM13740

GM13740 LCL from B-Lymphocyte

Description:

LEIGH SYNDROME; LS
ATP SYNTHASE 6; MTATP6

Affected:

Yes

Sex:

Male

Age:

12 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Carbohydrate Metabolism

Class

Disorders of the Mitochondrial Genome

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Mother and 3 sibs are also affected; developmental delay, dementia, ataxia, rod-cone dysfunction, vascular attenuation and peripheral mottling of the retinal pigment epithelium; homoplasmic mutant of ATPase 6 (MTATP6) , mtDNA 8993 T>G [Leu156Arg (L156R)]

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME

PCR analysis of DNA from this cell culture gave a positive result with a primer for Yq11, DYS227.

Gene

MTATP6

Chromosomal Location

Allelic Variant 1

516060.0001; LEIGH SYNDROME

Identified Mutation

LEU156ARG; Holt et al. [Am. J. Hum. Genet. 46: 428 (1990)] found a heteroplasmic T-to-G transversion at nucleotide pair 8993 in a maternal pedigree which resulted in the change of a hydrophobic leucine to a hydrophilic arginine at position 156 in subunit 6 of mitochondrial H(+)-ATPase. The clinical symptoms varied in proportion to the percentage of mutant mtDNAs but the most common clinical presentation included neurogenic muscle weakness, ataxia, and retinitis pigmentosa, leading to the designation of NARP (551500). The insertion of an arginine in the hydrophobic sequence of ATPase 6 probably interferes with the hydrogen ion channel formed by subunits 6 and 9 of the ATPase, thus causing failure of ATP synthesis. Tatuch et al. [Am. J. Hum. Genet. 50: 852 (1992)] and Shoffner et al. [Neurology 42: 2168 (1992)] demonstrated that the nucleotide 8993 mutation can cause Leigh disease.

Phenotypic Data

Remarks

Publications

Chin RM, Panavas T, Brown JM, Johnson KK, Patient-derived lymphoblastoid cell lines harboring mitochondrial DNA mutations as tool for small molecule drug discovery BMC research notes11:205 2018

PubMed ID: 29587845

, Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015) : Jeddah, Kingdom of Saudi Arabia 30 November - 3 December 2015 BMC genomics17 Suppl 6:487 2016

PubMed ID: 27454254

Dames S, Chou LS, Xiao Y, Wayman T, Stocks J, Singleton M, Eilbeck K, Mao R, The Development of Next-Generation Sequencing Assays for the Mitochondrial Genome and 108 Nuclear Genes Associated with Mitochondrial Disorders The Journal of molecular diagnostics : JMD17 Suppl 6:487 2013

PubMed ID: 23665194

Goldschmidt R, Arce PM, Khdour OM, Collin VC, Dey S, Jaruvangsanti J, Fash DM, Hecht SM, Effects of cytoprotective antioxidants on lymphocytes from representative mitochondrial neurodegenerative diseases Bioorganic & medicinal chemistry21:969-78 2012

PubMed ID: 23313093

Trounce I, Neill S, Wallace DC, Cytoplasmic transfer of the mtDNA nt 8993 T-->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc Natl Acad Sci U S A91:8334-8 1994

PubMed ID: 8078883

Ortiz RG, Newman NJ, Shoffner JM, Kaufman AE, Koontz DA, Wallace DC, Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Arch Ophthalmol111:1525-30 1993

PubMed ID: 8240109