Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Lee Jun C Wong, Robert K. Naviaux, Nicola Brunetti-Pierri, Qing Zhang, Eric S. Schmitt, Cavatina Truong, Margherita Milone, Bruce H. Cohen, Beverly Wical, Jaya Ganesh, Alice A. Basinger, Barbara K. Burton, Kathryn Swoboda, Donald L. Gilbert, Adeline Vanderver, Russell P. Saneto, Bruno Maranda, Georgianne Arnold, Jose E. Abdenur, Paula J. WatersWilliam C. Copeland

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalHuman Mutation
Volume29
Issue number9
DOIs
StatePublished - Sep 2008

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Mitochondrial Diseases
Inborn Genetic Diseases
Molecular Biology
Mutation
Diffuse Cerebral Sclerosis of Schilder
Alleles
Phenotype
Chronic Progressive External Ophthalmoplegia
Myoclonic Epilepsy
Muscular Diseases
Ataxia
Neurodegenerative Diseases
Introns
Sequence Analysis
Exons
Pathology
Muscles
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Wong, L. J. C., Naviaux, R. K., Brunetti-Pierri, N., Zhang, Q., Schmitt, E. S., Truong, C., ... Copeland, W. C. (2008). Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Human Mutation, 29(9). https://doi.org/10.1002/humu.20824

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. / Wong, Lee Jun C; Naviaux, Robert K.; Brunetti-Pierri, 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.

In: Human Mutation, Vol. 29, No. 9, 09.2008.

Research output: Contribution to journalArticle

Wong, LJC, Naviaux, RK, Brunetti-Pierri, N, Zhang, Q, Schmitt, ES, Truong, C, Milone, M, Cohen, BH, Wical, B, Ganesh, J, Basinger, AA, Burton, BK, Swoboda, K, Gilbert, DL, Vanderver, A, Saneto, RP, Maranda, B, Arnold, G, Abdenur, JE, Waters, PJ & Copeland, WC 2008, 'Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.', Human Mutation, vol. 29, no. 9. https://doi.org/10.1002/humu.20824
Wong LJC, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Human Mutation. 2008 Sep;29(9). https://doi.org/10.1002/humu.20824
Wong, Lee Jun C ; Naviaux, Robert K. ; Brunetti-Pierri, 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. / Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. In: Human Mutation. 2008 ; Vol. 29, No. 9.
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AU - Gilbert, Donald L.

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AU - Saneto, Russell P.

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