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Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India.

Abstract Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation.
PMID
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Authors

Mayor MeshTerms

Point Mutation

Keywords
Journal Title investigative ophthalmology & visual science
Publication Year Start




PMID- 28768321
OWN - NLM
STAT- MEDLINE
DA  - 20170802
DCOM- 20170811
LR  - 20170811
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Linking)
VI  - 58
IP  - 10
DP  - 2017 Aug 01
TI  - Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on
      Diverse Mitochondrial Haplogroups in India.
PG  - 3923-3930
LID - 10.1167/iovs.16-20695 [doi]
AB  - Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the
      most common maternally inherited mitochondrial disorders. Three mitochondrial DNA
      point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C
      (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% 
      of males and approximately 10% of females carrying these mutations develop optic 
      neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic
      background and environmental modifiers, are likely to contribute toward the
      observed incomplete penetrance and gender bias. We aimed to investigate whether
      mtDNA haplogroup influences LHON clinical expression in Indian patients harboring
      the m.11778G>A mutation. Methods: Detailed clinical assessment and complete
      mitochondrial genome sequencing was undertaken in 64 LHON families harboring the 
      m.11778G>A mutation. Mitochondrial haplogroup was assigned based on
      evolutionarily conserved mtDNA variations. Results: A total of 543 individuals
      (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A
      mutation were recruited to the study. The overall disease penetrance was 27.07%
      (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of
      248). The mtDNA haplogroup analysis revealed that all affected probands belonged 
      to different mtDNA haplogroups. No association between the m.11778G>A mutation
      and the background mtDNA haplogroup was detected. Conclusions: The first detailed
      study of Indian LHON patients confirm that the m.11778G>A-related LHON in India
      coexists with multiple different mtDNA haplogroups, unlike the preferential
      association of west Eurasian haplogroup J and the reported increased clinical
      penetrance with the J2 subhaplogroup. However, we observed variable penetrance of
      LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible 
      influence on clinical expression. These data suggest that a similar
      heterogeneity, resulting from the mtDNA haplogroup, might also exist in other
      mitochondrial diseases among Indian populations.
FAU - Khan, Nahid Akhtar
AU  - Khan NA
AD  - Council of Scientific and Industrial Research, Centre for Cellular and Molecular 
      Biology, Hyderabad, India.
FAU - Govindaraj, Periyasamy
AU  - Govindaraj P
AD  - Council of Scientific and Industrial Research, Centre for Cellular and Molecular 
      Biology, Hyderabad, India 2Department of Neurology, National Institute of Mental 
      Health and Neurosciences, Bengaluru, India 3Neuromuscular Laboratory,
      Neurobiology Research Centre, National Institute of Mental Health and
      Neurosciences, Bengaluru, India.
FAU - Soumittra, Nagasamy
AU  - Soumittra N
AD  - SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, 
      Sankara Nethralaya, Chennai, India.
FAU - Sharma, Sonika
AU  - Sharma S
AD  - Council of Scientific and Industrial Research, Centre for Cellular and Molecular 
      Biology, Hyderabad, India.
FAU - Srilekha, Sundaramoorthy
AU  - Srilekha S
AD  - SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, 
      Sankara Nethralaya, Chennai, India.
FAU - Ambika, Selvakumar
AU  - Ambika S
AD  - Department of Neuro-Ophthalmology, Medical Research Foundation, Sankara
      Nethralaya Chennai, India.
FAU - Vanniarajan, Ayyasamy
AU  - Vanniarajan A
AD  - Council of Scientific and Industrial Research, Centre for Cellular and Molecular 
      Biology, Hyderabad, India 6Department of Molecular Genetics, Aravind Medical
      Research Foundation, Madurai, India.
FAU - Meena, Angamuthu Kanikannan
AU  - Meena AK
AD  - Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
FAU - Uppin, Megha S
AU  - Uppin MS
AD  - Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India.
FAU - Sundaram, Challa
AU  - Sundaram C
AD  - Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India.
FAU - Bindu, Parayil Sankaran
AU  - Bindu PS
AD  - Department of Neurology, National Institute of Mental Health and Neurosciences,
      Bengaluru, India 3Neuromuscular Laboratory, Neurobiology Research Centre,
      National Institute of Mental Health and Neurosciences, Bengaluru, India.
FAU - Gayathri, Narayanappa
AU  - Gayathri N
AD  - Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of
      Mental Health and Neurosciences, Bengaluru, India 9Department of Neuropathology, 
      National Institute of Mental Health and Neurosciences, Bengaluru, India.
FAU - Taly, Arun B
AU  - Taly AB
AD  - Department of Neurology, National Institute of Mental Health and Neurosciences,
      Bengaluru, India 3Neuromuscular Laboratory, Neurobiology Research Centre,
      National Institute of Mental Health and Neurosciences, Bengaluru, India.
FAU - Thangaraj, Kumarasamy
AU  - Thangaraj K
AD  - Council of Scientific and Industrial Research, Centre for Cellular and Molecular 
      Biology, Hyderabad, India.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (DNA, Mitochondrial)
RN  - EC 1.6.5.3 (NADH dehydrogenase subunit 4)
RN  - EC 1.6.99.3 (NADH Dehydrogenase)
SB  - IM
MH  - Adult
MH  - Asian Continental Ancestry Group/*genetics
MH  - DNA Mutational Analysis
MH  - DNA, Mitochondrial/*genetics
MH  - Family
MH  - Female
MH  - Haplotypes/genetics
MH  - Humans
MH  - India/epidemiology
MH  - Male
MH  - Mitochondria/genetics
MH  - NADH Dehydrogenase/*genetics
MH  - Optic Atrophy, Hereditary, Leber/epidemiology/*genetics/pathology
MH  - Pedigree
MH  - *Point Mutation
MH  - Young Adult
EDAT- 2017/08/03 06:00
MHDA- 2017/08/12 06:00
CRDT- 2017/08/03 06:00
AID - 2647210 [pii]
AID - 10.1167/iovs.16-20695 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):3923-3930. doi:
      10.1167/iovs.16-20695.