Original Article
Investigation of the Mitochondrial ATPase 6/8 and tRNALys
Genes Mutations in Autism
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* Corresponding Address: P.O.Box: 14155-6343, Department of Medical Genetics, National Institute of Genetic Engineering
and Biotechnology (NIGEB), Tehran, Iran
Email: [email protected]
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Abstract
2EMHFWLYH Autism results from developmental factors that affect many or all functional
brain systems. Brain is one of tissues which are crucially in need of adenosine triphosphate (ATP). Autism is noticeably affected by mitochondrial dysfunction which impairs
energy metabolism. Considering mutations within ATPase 6, ATPase 8 and tRNALys genes,
associated with different neural diseases, and the main role of ATPase 6/8 in energy generation, we decided to investigate mutations on these mtDNA-encoded genes to reveal
their roles in autism pathogenesis.
0DWHULDOVDQG0HWKRGV In this experimental study, mutation analysis for the mentioned
JHQHVZHUHSHUIRUPHGLQDFRKRUWRIXQUHODWHGSDWLHQWVZLWKLGLRSDWKLFDXWLVPE\HPSOR\ing amplicon sequencing of mtDNA fragments.
5HVXOWV,QWKLVVWXG\SDWLHQWVVKRZHGSRLQWPXWDWLRQVWKDWUHSUHVHQWDVLJQL¿FDQWFRUUHODWLRQEHWZHHQDXWLVPDQGPW'1$YDULDWLRQV0RVWRIWKHLGHQWL¿HGVXEVWLWXWLRQV
ZHUHREVHUYHGRQMT-ATP6, altering some conserved amino acids to other ones
which could potentially affect ATPase 6 function. Mutations causing amino acid replacement
denote involvement of mtDNA genes, especially ATPase 6 in autism pathogenesis.
&RQFOXVLRQMtDNA mutations in relation with autism could be remarkable to realize an
understandable mechanism of pathogenesis in order to achieve therapeutic solutions.
Keywords: Autism, Mitochondria, Mutation, ATP ase6/8, tRNALys
Cell Journal(Yakhteh), Vol 14, No 2, Summer 2012, Pages: 98-101
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Introduction
Autism as a neurodevelopmental disorder is
diagnosed by three core-defining features: delayed social interaction, impaired verbal or
nonverbal communication and restricted and
repetitive behavior. This condition is categoUL]HGDVDPXOWLIDFWRULDOGLVHDVH5HJDUGOHVVRI
a strong genetic basis for autism, its genetics is
immensely complicated considering multigene
interactions or rare mutations with major effects
LQDXWLVPVSHFWUXPGLVRUGHUV$6''HYHORSmental factors that affect many functional brain
systems cause autism (2) and disturbance in the
SHUIHFWWLPLQJRIEUDLQGHYHORSPHQW
Autism is noticeably suggested to be affected
by mitochondrial dysfunction as a result of perturbations to mitochondrial structural proteins
DQG W51$V ZKLFK DUH HQFRGHG E\ PW'1$ 7KH
FRQFHSW ZKLFK KDG SRVHG WKDW PW'1$ G\VIXQFtion may contribute to develop autism led to fol-
CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012
98
Investigation of Mitochondrial Mutations in Autism
low-on investigations to find mutations which
would be causative factors in autism. Oliveira
HW DO H[SODLQHG REVHUYDWLRQ RI WKH FULWHULD
for respiratory chain disorders in 7% of schoolDJHFKLOGUHQZLWK$6'$FFRUGLQJWRWKHVWXG\
E\ 5DPR] HW DO DXWLVP VKRZV D VWURQJ DVsociation with single nucleotide polymorphisms
within the SLC25A12 JHQH 0RUHRYHU :HLVVPDQ HW DO KDV UHSRUWHG WKDW WKH HOHFWURQ
transport chain (ETC) complexes I and III deficiencies affect energy metabolism in patients
ZLWKDXWLVP$FFRUGLQJWR3RQVHWDOVWXG\
WKH $* PXWDWLRQ LQ tRNALeu 1 results in
PW'1$GHSOHWLRQ,QWKHVWXG\E\*UDIHWDORQ
a family with heterogeneous neurological disorGHUVZLWK*$LQtRNALys, a boy showed the
characteristics of autism, although no reports
have confirmed the certainty of this mutation
LQYROYHPHQW LQ DXWLVP LQ WKDW FKLOG &RQcerning the involvement of tRNAs mutations as
SRWHQWLDO ULVN IDFWRUV DQG WKH ATPase 6/8 role
in producing energy, the main objective of this
study was to identify mutations of considerable
importance in mitochondrial ATPase 6/8 and
tRNALys genes which indicate meaningful correlation with developing autism.
Materials and Methods
Subjects, samples and DNA extraction
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LQWKHDJHUDQJHZHUHUDQGRPO\REWDLQHG
who had been already ascertained with autism
by the specialists. The diagnosis of autism was
PDGH E\ 'LDJQRVWLF DQG 6WDWLVWLFDO 0DQXDO RI
0HQWDO'LVRUGHUVFULWHULD$XWLVP'LDJQRVWLF ,QWHUYLHZ5HYLVHG DQG $XWLVP 'LDJQRVWLF 2EVHUYDWLRQ 6FKHGXOH FKHFNOLVWV
respectively.
$OO WKH FDVHV ZHUH FKHFNHG IRU NQRZQ VHFRQGary causes of autism- additional inclusion criteria- by
physical examination (for detection of any dysmorSKLFIHDWXUHRUVNHOHWDODEQRUPDOLW\DVH[FOXVLRQFULWHULRQQHXURORJLFDOH[DPLQDWLRQEUDLQ05,)UDJLOH;DQG5HWWV\QGURPHPROHFXODUWHVWF\WRJHQHWLF
VWXG\HOHFWURHQFHSKDORJUDSK\YLVXDOHYRNHGSRWHQWLDOVDQGEUDLQVWHPDFRXVWLFHYRNHGUHVSRQVHPHWDEROLFVFUHHQLQJWHVWRQGULHGEORRGVDPSOHE\06
06DQGXULQHRUJDQLFDFLGVHYDOXDWLRQ
(YHQWXDOO\ FDVHV PDOHV DQG IHPDOHV
CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012
99
with inclusion criteria for primary autism were
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consents to the genetic analysis. The peripheral blood samples were obtained and genomic
'1$ZDVH[WUDFWHGXVLQJD'1$H[WUDFWLRQNLW
'LDWRP '1$ ([WUDFWLRQ .LW *HQHIDQDYDUDQ
7HKUDQ7KLVVWXG\ZDVDSSURYHGE\WKH%RDUG
of Ethics of National Institute of Genetic EnJLQHHULQJDQG%LRWHFKQRORJ\1,*(%7HKUDQ
Iran.
PW'1$DPSOL¿FDWLRQDQGVHTXHQFLQJ
In order to screen the mutations of MT-TK, MTATP6 and MT-ATP8JHQHVDPSOL¿FDWLRQZDVFDUULHGRXWXVLQJDVHWRISULPHUVDVIROORZV213)
DQG 2135 ÀDQNLQJ MT-NC7, MT-TK, MTATP6 and MT-ATP8 as one fragment. Then, the
3&5 UHDFWLRQV ZHUH SHUIRUPHG DV WKH SUHYLRXV
VWXG\3&5SURGXFWVZHUHVHSDUDWHO\HOHFWURSKRUHVHG WKURXJK DJDURVH WR LQVXUH
DQ VSHFLILF EDQG 7KH QXFOHRWLGH VHTXHQFHV RI
WKH DPSOLFRQV EHORQJHG WR SDWLHQWV ZHUH
GHWHUPLQHG E\ DXWRPDWHG VHTXHQFLQJ $%, PDFKLQH XVLQJ SULPHU 213) 0DFURgene Seoul, Korea) in search of mutations or
amino acid changes in tRNALys and ATPase 6/8.
7KH REWDLQHG PW'1$ VHTXHQFHV ZHUH DOLJQHG
ZLWK D PXOWLSOH VHTXHQFHV DOLJQPHQW LQWHUIDFH
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variations were confirmed by repeated analysis
of both strands.
Results
This study led us to identify 9 different point
PXWDWLRQVLQSDWLHQWVRXWRIRXUFDVHVRQ
MT-ATP 6, MT-ATP 8, MT-NC7 and some parts of
MT-COII genes which are shown in table 1. On
WKH$73DVHJHQHVWKH¿YHREVHUYHGPXWDWLRQV
UHVXOWHGLQDPLQRDFLGUHSODFHPHQWV0RVWRIWKHVH
VXEVWLWXWLRQV RFFXUUHG RQ MT-ATP6.
22.22% of point mutations were found on MTCOII and 11.11% of point mutations were noted
on each of MT-NC7 and ATPase 8. Some of these
subsitutions were similarly observed in different patients; albeit, more than one point mutation
ZHUHGHWHFWHGLQVRPHSDWLHQWV%DVHGRQVHTXHQFing result, all obsreved mutations were found to
EHKRPRSODVPLF1RPXWDWLRQVZHUHLGHQWL¿HGRQ
tRNALysLQSDWLHQWV
Piryaei et al.
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Nucleotide position
Locus
Amino acid change
Frequency (%)
Reported in other disease
G8251A
07&2
*ĺ*
G8269A
07&2
(in stop codon)
A8271G
071&
(in noncoding region)
C8472T
07$73
3ĺ/
C8684T
07$73
7ĺ,
(17)
G8697A
07$73
0ĺ,
A8701G
07$73
7ĺ$
A8836G
07$73
0ĺ9
(19)
G8865A
07$73
9ĺ9
(20)
G; Glycine, P; Proline, L; Lysine, T; Threonine, I; Isoleucine, M; Methionine, A; Alanine and V; Valine.
Discussion
In respiratory chain, a number of polypeptides which
DUHHQFRGHGZLWKFRRSHUDWLRQEHWZHHQPW'1$DQGQXFOHXVJDWKHUWRIRUPDGHOLFDWHVHULHVRIHQ]\PHFRPSOH[HVE\ZKLFK$73WKHPRVWYLWDOVRXUFHRIHQHUJ\
LV JHQHUDWHG &RPSOH[ 9 $73 V\QWKDVH DV WKH ODVW
HQ]\PHZKLFKGLUHFWO\SOD\VDSDUWLQSURGXFLQJ$73
LQFOXGHVVXEXQLWVRIZKLFKATPases 6 and 8 encodHGE\PW'1$$Q\HIIHFWLYHPXWDWLRQLQWKHVHVXEXQLWVFDXVHVORVVRI$73SURGXFWLRQLQWKHWLVVXHVZLWK
the highest demand of energy, such as brain and muscle
ZKLFKZRXOGFRQVHTXHQWO\JHWGDPDJHGDQGUHVXOWVLQ
human disease. ATPase 6LVNQRZQWREHDIDVWHYROYLQJ
gene (21); however, some disorders have been found
in association with mutations on ATPase 6. Since some
amino acid residues belonging to ATPase 6 are conserved in human species, any changes in these residues
are considered potentially pathogenic. In addition, some
residues which have been sustained in other mammals
DQG SURNDU\RWHV LQ FRPPRQ ZLWK KXPDQV DUH NQRZQ
as highly conserved. Therefore, replacing them with
other residues can be undoubtedly pathogenic because
of altering the tertiary structure of ATPase 6 (22). FurWKHUPRUHPW'1$HQFRGHVW51$JHQHVZKLFKDUH
QHFHVVDU\IRUPW'1$HQFRGHGSRO\SHSWLGHVV\QWKHVLV
hence, any mutation altering functional structures in the
PW'1$ FRGLQJ UHJLRQ GH¿QLWHO\ ZRXOG DIIHFW PLWRchondrial energy production.
,Q WKH SUHVHQW VWXG\ VLJQL¿FDQW DPRXQW RI PW'1$
YDULDWLRQVZHUHREVHUYHGDVSDWLHQWVVKRZHG
GLIIHUHQW VXEVWLWXWLRQV PXWDWLRQ $SSUR[LPDWHO\ RIWKHVHPXWDWLRQVZHUHLGHQWL¿HGLQATPase 6 while
RIWKHPOHGWRDPLQRDFLGUHSODFHPHQWV,WLVQRWHG
WKDW*$ZHUHGHWHFWHGLQRIRXUSDWLHQWV
ZKLFKOHGWRFKDQJHIURPPHWKLRQLQH0HWto isoleu-
sine (Ile). 0HWLVDFRQVHUYHGUHVLGXHLQLWVSRVLWLRQ,Q
addition, it, as a sulphur-containing amino acid, is usually found hidden within proteins and has a tendency to
IRUPȕVKHHWV'HVSLWHKDYLQJDK\GURSKRELFSURSHUW\
it is able to react with some electrophilic centers. On
WKHFRQWUDU\,OHDERXQGVLQĮKHOL[HVDQGSOD\VDUROH
in ligand binding to proteins. So, structure and function of ATPase 6DUHYHU\OLNHO\WRXQGHUJRDFKDQJHLQ
VXFKUHSODFHPHQW6XEVWLWXWLRQDWSRVLWLRQRQHRI
highly conserved nucleotides, was another point mutaWLRQZKLFKZDVLGHQWL¿HGWRUHSODFH0HWWRYDOLQH9DO
LQRIFDVHV6LPLODUWR,OH9DOZLWKDYHU\VPDOO
VLGHFKDLQLVIRXQGDEXQGDQWO\LQĮKHOL[VWUXFWXUHV,Q
WKHVDPHSDWLHQWV&7OHGLQWRQRQSRODUSUROLQH
3URWRSRODUO\VLQH/\VUHSODFHPHQW3URLVRIWHQREVHUYHGDWWKHHQGRIKHOL[WXUQVRUORRSV%HLQJVLWXDWHG
3URLQDKHOL[WKHKHOL[ZLOOKDYHDVOLJKWEHQGGXHWR
WKHODFNRIWKHK\GURJHQERQG$OVR3URFDQH[LVWLQWKH
FLVFRQ¿JXUDWLRQLQSHSWLGHVLQFRQWUDVWWRRWKHUDPLQR
acids which are found exclusively in the trans- form in
SRO\SHSWLGHV 6R FLVWUDQV LVRPHUL]DWLRQ FDQ SOD\ DQ
important role in the folding of proteins. In Lys, the
amino group is greatly reactive and often participates in
reactions at the active centers. These two amino acids
are entirely different in their chemical properties. Thus,
this replacement can cause inappropriate interaction
between this position and other residues that ultimately
could result in ATPase 8 malfunction .There were not
DQ\PXWDWLRQVLGHQWL¿HGRQtRNALysLQSDWLHQWV$VD
UHVXOWVXEVWLWXWLRQ*$LVQRWOLNHO\WREHDSRWHQWLDOULVNIDFWRULQDXWLVP
Indication of previous researches strengthen the hySRWKHVLVWKDWGH¿FLHQFLHVLQHDFKRIPLWRFKRQGULDOIXQFtional components lead to defective energy metabolism
in autism. On the other hand, mitochondria perform an
CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012
100
Investigation of Mitochondrial Mutations in Autism
essential role in the generation of reactive oxygen speFLHV526ZKLFKFDQUHVXOWLQJHQHWLFLQVWDELOLW\
E\R[LGDWLYHVWUHVVDQG'1$GDPDJH,QWKLVSRLQW
of view, we analysed ATPase 6/8 mutations which can
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with our result. ATPase 6/8 genes have been investigated in different neurodegenerative diseases, such as
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$7)ULHGUHLFK¶V$WD[LD)$0XOWLSOH6FOHURVLV 06 DQG 6SLQR &HUHEHOODU$WD[LDV 6&$
*$KDVEHHQLGHQWL¿HGLQSDWLHQWVZLWK$7
06DQG6&$FDXVLQJDFRQVHUYHGDPLQRDFLGUHSODFHPHQW$QRWKHUVXEVWLWXWLRQDWKDVEHHQREVHUYHG
LQSDWLHQWVZLWK+'06)$DQG6&$$OOWKHVH¿QGLQJV VXJJHVW WKDW WKH PW'1$ PXWDWLRQV PLJKW EH LQvolved in pathogenesis of mitochondrial dysfunction in
neural disorders.
7.
8.
9.
11.
12.
Conclusion
15.
2XUGDWDVKRZHGDUHODWLRQEHWZHHQLQFUHDVHGPW'1$YDULDWLRQVDQGDXWLVP+RZHYHUSDWKRJHQHVLVRI
autism as a multifactorial disorder is much more comSOLFDWHGWKDQLWVHHPV:HVXJJHVWIROORZXSSRSXODtion and haplogroup studies in order to achieve more
information about whether these substitutions are
polymorphisms or pathogenic mutations.
Acknowledgements
:HZRXOGOLNHWRWKDQNWKHSDWLHQWVDQGWKHLUSK\VLcians for collaboration with the study. This research
has been carried out at National Institute of Genetic
(QJLQHHULQJDQG%LRWHFKQRORJ\1,*(%DVDUHVXOW
RI06FVWXGHQW¶VJUDGXDWLRQUHVHDUFKSURMHFW:HDUH
JUDWHIXO WR RXU FROOHJXHV LQ 6SHFLDO 0HGLFDO &HQWHU
for their assistance. The authors declare that they have
no competing interests.
2.
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