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Molecular and clinical genetics of mitochondrial diseases due to POLG mutations
Author(s) -
Wong LeeJun C.,
Naviaux Robert K.,
BrunettiPierri Nicola,
Zhang Qing,
Schmitt Eric S.,
Truong Cavatina,
Milone Margherita,
Cohen Bruce H.,
Wical Beverly,
Ganesh Jaya,
Basinger Alice A.,
Burton Barbara K.,
Swoboda Kathryn,
Gilbert Donald L.,
Vanderver Adeline,
Saneto Russell P.,
Maranda Bruno,
Arnold Georgianne,
Abdenur Jose E.,
Waters Paula J.,
Copeland William C.
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20824
Subject(s) - biology , genetics , mitochondrial disease , missense mutation , ataxia , mitochondrial encephalomyopathies , allele , compound heterozygosity , mutation , mitochondrial myopathy , mitochondrial dna , exon , genetic heterogeneity , phenotype , gene , neuroscience
Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time‐dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG‐ related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG ‐related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans , finding deleterious mutations can provide an unequivocal diagnosis of the disease. Published 2008 Wiley‐Liss, Inc.