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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. ljwong@bcm.edu
Lee-Jun C
LJ
Wong
Robert K
RK
Naviaux
Nicola
N
Brunetti-Pierri
Qing
Q
Zhang
Eric S
ES
Schmitt
Cavatina
C
Truong
Margherita
M
Milone
Bruce H
BH
Cohen
Beverly
B
Wical
Jaya
J
Ganesh
Alice A
AA
Basinger
Barbara K
BK
Burton
Kathryn
K
Swoboda
Donald L
DL
Gilbert
Adeline
A
Vanderver
Russell P
RP
Saneto
Bruno
B
Maranda
Georgianne
G
Arnold
Jose E
JE
Abdenur
Paula J
PJ
Waters
William C
WC
Copeland
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