<p>Dear Sir,</p> <p>Alzheimer′s disease (AD) is a neurodegenerative disorder characterized by a gradual loss of episodic memory, <sup> <xref ref-type="bibr" rid="ref1">1</xref> </sup>in which an interplay between genes and environmental factors are involved. A variety of genetic, medical and environmental factors <sup> <xref ref-type="bibr" rid="ref2">2</xref> </sup>modulate the ageing-related processes leading to the devastation of the brain in AD. <sup> <xref ref-type="bibr" rid="ref3">3</xref> </sup>Mutations in mitochondrial DNA (mtDNA) are suspected to be causally related, since mtDNA is maternally inherited in a non-Mendelian way. <sup> <xref ref-type="bibr" rid="ref4">4</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref5">5</xref> </sup>In this study (research project number #15), the mtDNA of 24 AD patients and 100 healthy controls from peripheral blood samples collected from Special Medical Center of Tehran, Iran during 2010-2011 were investigated using Plymerase Chain Reaction (PCR) <sup> <xref ref-type="bibr" rid="ref6">6</xref> </sup>and sequencing methods. The ethical approval and patient informed consent was obtained for the genetic analysis.</p> <p>Fifteen variations were found in different tRNA mtDNA, where eleven variations were polymorphic mutations. A12308G, a polymorphic mutation (tRNA Leu [CUN]), was found in 8 patients. This mutation was reported in different neurodegenerative diseases as well as in controls. However, four variations {C1631A, T1633A (tRNA Val), T14704C and T14723C (tRNA Glu)} fulfilled the criteria for pathogenic mutations, such as a heteroplasmic state, conserved nucleotides, not reported in previous literature and not found in healthy controls. We believe that these variations may have pathogenic effects in AD or have secondary effects in the disease process. The percentage of heteroplasmic mutations may play a role in the signs and symptoms or age of onset of AD.</p> </sec> </body> <back> <ref-list> <ref id="ref1"> <label>1</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Mucke</surname> <given-names>L</given-names> </name> </person-group> <article-title>Neuroscience: Alzheimer′s disease</article-title> <source>Nature</source> <year>2009</year> <volume>461</volume> <fpage>895</fpage> <lpage>97</lpage> </nlm-citation> </ref> <ref id="ref2"> <label>2</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Welsh-Bohmer</surname> <given-names>KA</given-names> </name> <name> <surname>Plassman</surname> <given-names>BL</given-names> </name> <name> <surname>Hayden</surname> <given-names>KM</given-names> </name> </person-group> <article-title>Genetic and environmental contributions to cognitive decline in aging and Alzheimer′s disease</article-title> <source>Annu Rev Gerontol Geriatr</source> <year>2010</year> <volume>30</volume> <fpage>81</fpage> <lpage>114</lpage> </nlm-citation> </ref> <ref id="ref3"> <label>3</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Heininger</surname> <given-names>K</given-names> </name> </person-group> <article-title>A unifying hypothesis of Alzheimer′s disease.II</article-title> <source>Pathophysiological processes</source> <year></year> <volume></volume> <fpage></fpage> <comment>A unifying hypothesis of Alzheimer's disease II Pathophysiological processes Hum Psychopharmacol 1999;14:525-81</comment> </nlm-citation> </ref> <ref id="ref4"> <label>4</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Giles</surname> <given-names>RE</given-names> </name> <name> <surname>Blanc</surname> <given-names>H</given-names> </name> <name> <surname>Cann</surname> <given-names>HM</given-names> </name> <name> <surname>Wallace</surname> <given-names>DC</given-names> </name> </person-group> <article-title>Maternal inheritance of human mitochondrial DNA</article-title> <source>Proc Natl Acad Sci USA</source> <year>1980</year> <volume>77</volume> <fpage>6715</fpage> <lpage>9</lpage> </nlm-citation> </ref> <ref id="ref5"> <label>5</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Hamblet</surname> <given-names>NS</given-names> </name> <name> <surname>Castora</surname> <given-names>FJ</given-names> </name> </person-group> <article-title>Elevated levels of the Kearns-Sayre syndrome mitochondrial DNA deletion in temporal cortex of Alzheimer′s patients</article-title> <source>Mutat Res</source> <year>1997</year> <volume>379</volume> <fpage>253</fpage> <lpage>62</lpage> </nlm-citation> </ref> <ref id="ref6"> <label>6</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Houshmand</surname> <given-names>M</given-names> </name> <name> <surname>Larsson</surname> <given-names>NG</given-names> </name> <name> <surname>Holme</surname> <given-names>E</given-names> </name> <name> <surname>Oldfors</surname> <given-names>A</given-names> </name> <name> <surname>Tulinius</surname> <given-names>MH</given-names> </name> <name> <surname>Andersen</surname> <given-names>O</given-names> </name> </person-group> <article-title>Automatic sequencing of mitochondrial tRNA genes in patients with mitochondrial encephalomyopathy</article-title> <source>Biochim Biophys Acta</source> <year>1994</year> <volume>1226</volume> <fpage>49</fpage> <lpage>55</lpage> </nlm-citation> </ref> <ref id="ref7"> <label>7</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"></person-group> <article-title></article-title> <source></source> <year></year> <volume></volume> <fpage></fpage> </nlm-citation> </ref> </ref-list> </back> </article>

JRMS

J Res Med Sci

Journal of Research in Medical Sciences

1735-1995 1735-7136

Medknow Publications Pvt Ltd

India

JRMS-18-269

23930130

10.4103/0975-2870.114677

Letter to Editor

New pathogenic variations of mitochondrial DNA in Alzheimer disease!!

Nia

Samira S

Azadfar

Parisa

Akbari

Leila

Assarzadegan

Farhad

Kamalidehghan

Behnam

Maroof

Hamid R

Houshmand

Massoud

Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran Department of Neurology, Imam Hossein Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Department of Medical Genetic, Special Medical Center, Tehran, Iran Department of Medical Genetic, Special Medical Center; Department of Medical Genetic National Institute of Genetic Engineering and Biotechnology, Tehran, Iran

Address for correspondence:Massoud Houshmand, Department of Medical Genetic, National Institute of Genetic Engineering and Biotechnology,Tehran, Iran massoudh@nigeb.ac.ir

March 2013

18 3 269 269

2013

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

<p>Dear Sir,</p> <p>Alzheimer′s disease (AD) is a neurodegenerative disorder characterized by a gradual loss of episodic memory, <sup> <xref ref-type="bibr" rid="ref1">1</xref> </sup>in which an interplay between genes and environmental factors are involved. A variety of genetic, medical and environmental factors <sup> <xref ref-type="bibr" rid="ref2">2</xref> </sup>modulate the ageing-related processes leading to the devastation of the brain in AD. <sup> <xref ref-type="bibr" rid="ref3">3</xref> </sup>Mutations in mitochondrial DNA (mtDNA) are suspected to be causally related, since mtDNA is maternally inherited in a non-Mendelian way. <sup> <xref ref-type="bibr" rid="ref4">4</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref5">5</xref> </sup>In this study (research project number #15), the mtDNA of 24 AD patients and 100 healthy controls from peripheral blood samples collected from Special Medical Center of Tehran, Iran during 2010-2011 were investigated using Plymerase Chain Reaction (PCR) <sup> <xref ref-type="bibr" rid="ref6">6</xref> </sup>and sequencing methods. The ethical approval and patient informed consent was obtained for the genetic analysis.</p> <p>Fifteen variations were found in different tRNA mtDNA, where eleven variations were polymorphic mutations. A12308G, a polymorphic mutation (tRNA Leu [CUN]), was found in 8 patients. This mutation was reported in different neurodegenerative diseases as well as in controls. However, four variations {C1631A, T1633A (tRNA Val), T14704C and T14723C (tRNA Glu)} fulfilled the criteria for pathogenic mutations, such as a heteroplasmic state, conserved nucleotides, not reported in previous literature and not found in healthy controls. We believe that these variations may have pathogenic effects in AD or have secondary effects in the disease process. The percentage of heteroplasmic mutations may play a role in the signs and symptoms or age of onset of AD.</p> </sec> </body> <back> <ref-list> <ref id="ref1"> <label>1</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Mucke</surname> <given-names>L</given-names> </name> </person-group> <article-title>Neuroscience: Alzheimer′s disease</article-title> <source>Nature</source> <year>2009</year> <volume>461</volume> <fpage>895</fpage> <lpage>97</lpage> </nlm-citation> </ref> <ref id="ref2"> <label>2</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Welsh-Bohmer</surname> <given-names>KA</given-names> </name> <name> <surname>Plassman</surname> <given-names>BL</given-names> </name> <name> <surname>Hayden</surname> <given-names>KM</given-names> </name> </person-group> <article-title>Genetic and environmental contributions to cognitive decline in aging and Alzheimer′s disease</article-title> <source>Annu Rev Gerontol Geriatr</source> <year>2010</year> <volume>30</volume> <fpage>81</fpage> <lpage>114</lpage> </nlm-citation> </ref> <ref id="ref3"> <label>3</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Heininger</surname> <given-names>K</given-names> </name> </person-group> <article-title>A unifying hypothesis of Alzheimer′s disease.II</article-title> <source>Pathophysiological processes</source> <year></year> <volume></volume> <fpage></fpage> <comment>A unifying hypothesis of Alzheimer's disease II Pathophysiological processes Hum Psychopharmacol 1999;14:525-81</comment> </nlm-citation> </ref> <ref id="ref4"> <label>4</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Giles</surname> <given-names>RE</given-names> </name> <name> <surname>Blanc</surname> <given-names>H</given-names> </name> <name> <surname>Cann</surname> <given-names>HM</given-names> </name> <name> <surname>Wallace</surname> <given-names>DC</given-names> </name> </person-group> <article-title>Maternal inheritance of human mitochondrial DNA</article-title> <source>Proc Natl Acad Sci USA</source> <year>1980</year> <volume>77</volume> <fpage>6715</fpage> <lpage>9</lpage> </nlm-citation> </ref> <ref id="ref5"> <label>5</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Hamblet</surname> <given-names>NS</given-names> </name> <name> <surname>Castora</surname> <given-names>FJ</given-names> </name> </person-group> <article-title>Elevated levels of the Kearns-Sayre syndrome mitochondrial DNA deletion in temporal cortex of Alzheimer′s patients</article-title> <source>Mutat Res</source> <year>1997</year> <volume>379</volume> <fpage>253</fpage> <lpage>62</lpage> </nlm-citation> </ref> <ref id="ref6"> <label>6</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"> <name> <surname>Houshmand</surname> <given-names>M</given-names> </name> <name> <surname>Larsson</surname> <given-names>NG</given-names> </name> <name> <surname>Holme</surname> <given-names>E</given-names> </name> <name> <surname>Oldfors</surname> <given-names>A</given-names> </name> <name> <surname>Tulinius</surname> <given-names>MH</given-names> </name> <name> <surname>Andersen</surname> <given-names>O</given-names> </name> </person-group> <article-title>Automatic sequencing of mitochondrial tRNA genes in patients with mitochondrial encephalomyopathy</article-title> <source>Biochim Biophys Acta</source> <year>1994</year> <volume>1226</volume> <fpage>49</fpage> <lpage>55</lpage> </nlm-citation> </ref> <ref id="ref7"> <label>7</label> <nlm-citation citation-type="journal"> <person-group person-group-type="author"></person-group> <article-title></article-title> <source></source> <year></year> <volume></volume> <fpage></fpage> </nlm-citation> </ref> </ref-list> </back> </article>