Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.
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.
Wong
Lee-Jun C
LJ
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. ljwong@bcm.edu
Naviaux
Robert K
RK
Brunetti-Pierri
Nicola
N
Zhang
Qing
Q
Schmitt
Eric S
ES
Truong
Cavatina
C
Milone
Margherita
M
Cohen
Bruce H
BH
Wical
Beverly
B
Ganesh
Jaya
J
Basinger
Alice A
AA
Burton
Barbara K
BK
Swoboda
Kathryn
K
Gilbert
Donald L
DL
Vanderver
Adeline
A
Saneto
Russell P
RP
Maranda
Bruno
B
Arnold
Georgianne
G
Abdenur
Jose E
JE
Waters
Paula J
PJ
Copeland
William C
WC
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics; D010641:Phenotype
D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human