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Exome sequencing found a novel homozygous deletion in ADCK3 gene involved in autosomal recessive spinocerebellar ataxia
Gene 708 (2019) 10–13
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Research paper
Exome sequencing found a novel homozygous deletion in ADCK3 gene involved in autosomal recessive spinocerebellar ataxia ⁎
T
⁎⁎
Mohammadreza Hajjaria, Maryam Tahmasebi-Birganib, , Javad Mohammadi-aslb,c, , Habib Nasirid, Abolghasem Kollaeec, Mandana Mahmoodic, Hossein Ansarie a
Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences c Noor Genetics Lab., Ahvaz, Iran d Pediatric Department, Ahvaz Jundishapur University of Medical Sciences, Golestan Hospital, Golestan, Ahvaz, Iran e Department of Biotechnology, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Autosomal recessive cerebellar ataxia Whole exome sequencing ADCK3 gene Deletion
Autosomal recessive cerebellar ataxia is heterogeneous inherited neurodegenerative disorders with more than 70 involved genes. The development of next generation sequencing opens a new window in rapid diagnosis of such heterogeneous condition in medical genetics laboratories. Here, we present ADCK3; del.CD (229–230) mutation in an Iranian consanguineous family with three cerebellar ataxic boys using whole exome sequencing. The mutation was predicted pathogenic and all the affected individuals were homozygous for the variant. Although, the ADCK3 was previously reported as one of the master genes of ARSC, our mutation was novel as has been not previously reported in dbSNP or literature.
1. Introduction Ataxia is a group of neurological conditions in which development of cerebellum or spinal cord has been impaired due to mitochondria dysfunction, metabolic disease or repair system deficiency (Palau and Espinós, 2006). Inherited forms of ataxia shows autosomal recessive, autosomal dominant or X-linked patterns (Palau and Espinós, 2006). Autosomal recessive form is usually congenital, non-progressive with early-onset appearance and clinically diagnosed with ataxia, epilepsy, endocrine manifestation and cognitive problems (Sailer and Houlden, 2012). More than 70 genes have been discovered for recessive form (Wiethoff et al., 2016). However, dominant forms are late-onset and progressive with high degree of genetic heterogeneity like recessive one (Jen et al., 2006). This also true in case of x-linked ataxia and several causative-genes have been reported until now (Apak et al., 1989). Nowadays, exome sequencing is a promising strategy to identify the genetic basis of mendelian disorders of unknown cause especially those suffering from with genetic heterogeneity (Ng et al., 2010). Here, we present a novel deletion in ADCK3 gene in an Iranian family of ARSC.
Several mutations in ADCK3 have been reported in the literature and introduced this gene as one the important gene in pathogenesis of ARSC. 2. Material and methods An Iranian family with three affected boys with symptoms of spinocerebellar atrophy ataxia from consanguineous marriage was included in this study (Fig. 1). The deceased grandfather also had ataxia and died at age 52. He showed the decreased coordination of hands and speech gradually and the MRI was abnormal and showed the cerebellar atrophy. The family did not have more information as several years passed. However, for all three brothers, MRI study was performed through the brain and cerebellar atrophy as sulsal dilation, prominent fulia was evidenced. Poor coordination of hands and walking was also observed in these brothers. Karyotype analysis was normal for all three affected boys. Informed written consent was obtained from the family and the study was ethnically approved by Shahid Chamran University of Ahvaz. The blood
Abbreviations: ARSC, Autosomal recessive cerebellar ataxia; NGS, Next Generation Sequencing; PCR, Polymerase chain reaction; SNP, Single nucleotide Polymorphism; WES, Whole exome sequencing ⁎ Correspondence to: M. Tahmasebi-Birgani, Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences. ⁎⁎ Correspondence to: J. Mohammadi-Asl, Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences and Noor Genetics Lab, Iran. E-mail addresses: [email protected] (M. Tahmasebi-Birgani), [email protected] (J. Mohammadi-asl). https://doi.org/10.1016/j.gene.2019.05.016 Received 23 October 2018; Received in revised form 19 April 2019; Accepted 6 May 2019 Available online 10 May 2019 0378-1119/ © 2019 Published by Elsevier B.V.
Gene 708 (2019) 10–13
M. Hajjari, et al.
Fig. 1. The pedigree of an Iranian family with symptoms of autosomal recessive spinocerebellar ataxia (ARSC). Four patients were clinically diagnosed as ARSC and the individual V-II represents the index patient.
4. Discussion
Table 1 The list of used primers in this study. Primer name
Primer sequence
ADCK3-Forward ADCK3-Reverse
5′-GTGGAGTGGGGGATTCCT-3′ 5′-CCCCTCTAAAGCAGGTCAATC-3′
Here we report a novel mutation in ADCK3 gene in an Iranian family suffering from ARSC using whole exome sequencing. The mutation is pathogenic deletion of amino acids 229–230 of ADCK3 gene which were detected in all affected individuals of the pedigree. The mutation was novel and has been not previously reported in dbSNP or literature. The father carried the mutation and has been probably received it from his father who were diagnosed for cerebellar ataxia too. The human AarF domain containing kinase 3A (ADCK3 or COQ8A) is located on 1q42.13. The gene encodes a membrane protein with electron transfer activity in mitochondrial respiratory chain (Iiizumi et al., 2002). The ADCK3 is one the 13reported genes involved in coenzyme Q (COQ) biosynthesis and cells carrying the mutation in ADCK3, will been countered with significant reduction in their COQ level which eventually disturbed the mitochondrial hemostasis (Cullen et al., 2016). The coenzyme Q is a critical lipophilic factor during oxidative phosphorylation pathway in mitochondria (Iiizumi et al., 2002). It has also demonstrated that expression of human ADCK3can rescue the COQ deficiency symptom in yeast COQ8 mutant model (Xie et al., 2011). The association of ADCK3 gene mutation with recessive ataxia syndrome was firstly described by SNP-array and linkage analysis of a large consanguineous family for childhood-onset recessive ataxia ended to find ADCK3 locus as novel gene of ARSC. The mutation was a donor splice-site c.1398 + 2T > C in intron 11 of ADCK3 gene (Lagier-Tourenne et al., 2008). Consequently, the ADCK3D420Wfs, Q167Lfs, Y514C, T584del, L314_Q369del, G549S, E551K, R213W, G272 V, G272D, N465Dfs, R348X, R348X, L379X, R271C, A304T, A304V, R299W and Y429C mutations reported for childhood, juvenile and adult-onset cases of cerebellar ataxia (Liu et al., 2014). In 2010, Gerards et al. reported two nonsense mutations including c.1136 T > A and c.1042 C > T in ADCK3 in a Dutch family of cerebellar ataxia (Gerards et al., 2010). In overall and until 2014, the association of ADCK3 mutations has been documented in 21 patients from 15 different ethnic groups, all of them showing the manifestation of ataxic cerebellar atrophy (Doimo et al., 2014). In 2014, using WES in an English patient of cerebellar atrophy, Liu et al. found a novel frameshift mutation in ADCK3 p.ser616fs* which leads to extend the protein polypeptide chain by losing the stop codon (Liu et al., 2014). In an
Amplicon size (bp) 500
samples were collected from all affected boys and their available family members and genomic DNA was extracted using salting out protocol. The DNA of one the affected individuals (V-II) were considered for WES analysis (Macrogen, South Korea). The WES-variants were filtered and the pathogenicity of the candidate variant was evaluated using in silico software. Segregation of the mutation through the pedigree was considered by PCR-amplification of DNA around the mutation site using specific primers (Table 1). The PCR amplicon were the sequenced by the same primers and Big Dye Terminators (Applied Bio systems 3130 Genetic Analyzer; Applied Bio systems, Foster City, CA, USA).
3. Results Around 95,572 variants were read in WES. Following the variant calls filtering, an inframe deletion c.685-690 delCTGGCA was found in ADCK3 gene (cDNA.806_811delCTGGCA and g.79943_79948delCTGGCA) of proband (III-VI). The mutation was existed in coding sequence (CDS) of the gene and resulted in deletion Leu229 and Ala 230 (Leu229 Ala 230 del). The candidate variant was novel and was not previously reported elsewhere. In silico analysis predicted the mutation as pathogenic. The variant was near the conserved domain Activator of bc1 complex (ABC1) kinases or aarF domain containing kinase 3 spanning from amino acid 295–545. All the affected brothers (II-2 and II-3) were homozygous for c.685-690 delCTGGCA variant. Although the proband's mother was died, the father was heterozygous for the mutation. Similar to the father, the sister (III-1) was also heterozygous for the candidate variant. The father was carrier of the mutation and has been probably received the mutation from his affected father (Fig. 2).
11
Gene 708 (2019) 10–13
M. Hajjari, et al.
Fig. 2. Sanger sequencing confirmed that ADCK3; del. CD (229–230) variant in all patients of family (a–c). Red and blue boxes show the flanking regions of deletion and deletion site respectively. Evaluation of the presence of WES-extracted pathogenic variant at conserved domain ADCK3 protein (d). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Conflict of interest
American adult-onset cerebellar ataxia patient, Malgireddy and his colleagues reported 2.9 Mb duplication at chromosome region 1q42.11q42.13where the ADCK3 is located (Malgireddy et al., 2017). Similarly, Ozcoraet al. identified the homozygous pathogenic variant p.Ala338Val in ADCK3using whole-exome sequencing in a case of cerebellar ataxia (Ozcora et al., 2017).
The authors declare no conflict of interest. References Apak, S., Yüksel, M., Özmen, M., Saka, N., Darendeliler, F., Neuhäuser, G., 1989. Heterogeneity of X-linked recessive (Spino) cerebellar ataxia with or without spastic diplegia. Am. J. Med. Genet. A 34 (2), 155–158. Cullen, J.K., Murad, N.A., Yeo, A., et al., 2016. Correction: AarF Domain Containing Kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation. PLoS One 11 (7), e0160162. Doimo, M., Desbats, M.A., Cerqua, C., Cassina, M., Trevisson, E., Salviati, L., 2014. Genetics of coenzyme q10 deficiency. Molecular syndromology 5 (3–4), 156–162. Gerards, M., van den Bosch, B., Calis, C., et al., 2010. Nonsense mutations in CABC1/ ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10 (5), 510–515. Iiizumi, M., Arakawa, H., Mori, T., Ando, A., Nakamura, Y., 2002. Isolation of a novel gene, CABC1, encoding a mitochondrial protein that is highly homologous to yeast activity of bc1 complex. Cancer Res. 62 (5), 1246–1250. Jen, J., Lee, H., Cha, Y., Nelson, S., Baloh, R., 2006. Genetic heterogeneity of autosomal dominant nonprogressive congenital ataxia. Neurology 67 (9), 1704–1706. Lagier-Tourenne, C., Tazir, M., López, L.C., et al., 2008. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q 10 deficiency. Am. J. Hum. Genet. 82 (3), 661–672. Liu, Y.T., Hersheson, J., Plagnol, V., et al., 2014. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J. Neurol. Neurosurg. Psychiatry 85 (5), 493–498. Malgireddy, K., Thompson, R., Torres-Russotto, D., 2017. A novel CABC1/ADCK3 mutation in adult-onset cerebellar ataxia (P6. 021). Neurology 88 (16 Supplement) (P6. 021). Ng, S.B., Buckingham, K.J., Lee, C., et al., 2010. Exome sequencing identifies the cause of
5. Conclusion In conclusion, the results of previous study on ADCK3in pathogenesis of cerebellar ataxia as well as the data obtained at this study indicates that ADCK3 and the mutations that occur in it play an important role in the development of this disease. Additionally, if the ataxic patients confirmed for ADCK3 mutation, they can start COQ therapy.
Acknowledgment The authors are contributed to the manuscript as MRH: Data collection and analysis, JMA: Data collection, MTB: Manuscript preparation and data analysis, HN, AK and MH: data collection. All the authors appreciated all friends and colleagues at Noor medical genetics laboratory specially Neda Golchin and Alireza Masbi for their generous assistants. The grant was supported by Shahid Chamran University of Ahvaz (Grant number# 842) and Noor genetic Laboratory, Ahvaz. 12
Gene 708 (2019) 10–13
M. Hajjari, et al.
Wiethoff, S., Hersheson, J., Bettencourt, C., Wood, N.W., Houlden, H., 2016. Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations. J. Neurol. 263 (8), 1503–1510. Xie, L.X., Hsieh, E.J., Watanabe, S., et al., 2011. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1811 (5), 348–360.
a mendelian disorder. Nat. Genet. 42 (1), 30. Ozcora, G.D.K., Basak, N., Canpolat, M., Acer, H., Kumandas, S., 2017. Coenzyme Q10 deficiency; a treatable autosomal recessive cerebellar ataxias. Eur. J. Paediatr. Neurol. 21, e136. Palau, F., Espinós, C., 2006. Autosomal recessive cerebellar ataxias. Orphanet journal of rare diseases 1 (1), 47. Sailer, A., Houlden, H., 2012. Recent advances in the genetics of cerebellar ataxias. Current neurology and neuroscience reports 12 (3), 227–236.
13
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Research paper
Exome sequencing found a novel homozygous deletion in ADCK3 gene involved in autosomal recessive spinocerebellar ataxia ⁎
T
⁎⁎
Mohammadreza Hajjaria, Maryam Tahmasebi-Birganib, , Javad Mohammadi-aslb,c, , Habib Nasirid, Abolghasem Kollaeec, Mandana Mahmoodic, Hossein Ansarie a
Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences c Noor Genetics Lab., Ahvaz, Iran d Pediatric Department, Ahvaz Jundishapur University of Medical Sciences, Golestan Hospital, Golestan, Ahvaz, Iran e Department of Biotechnology, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Autosomal recessive cerebellar ataxia Whole exome sequencing ADCK3 gene Deletion
Autosomal recessive cerebellar ataxia is heterogeneous inherited neurodegenerative disorders with more than 70 involved genes. The development of next generation sequencing opens a new window in rapid diagnosis of such heterogeneous condition in medical genetics laboratories. Here, we present ADCK3; del.CD (229–230) mutation in an Iranian consanguineous family with three cerebellar ataxic boys using whole exome sequencing. The mutation was predicted pathogenic and all the affected individuals were homozygous for the variant. Although, the ADCK3 was previously reported as one of the master genes of ARSC, our mutation was novel as has been not previously reported in dbSNP or literature.
1. Introduction Ataxia is a group of neurological conditions in which development of cerebellum or spinal cord has been impaired due to mitochondria dysfunction, metabolic disease or repair system deficiency (Palau and Espinós, 2006). Inherited forms of ataxia shows autosomal recessive, autosomal dominant or X-linked patterns (Palau and Espinós, 2006). Autosomal recessive form is usually congenital, non-progressive with early-onset appearance and clinically diagnosed with ataxia, epilepsy, endocrine manifestation and cognitive problems (Sailer and Houlden, 2012). More than 70 genes have been discovered for recessive form (Wiethoff et al., 2016). However, dominant forms are late-onset and progressive with high degree of genetic heterogeneity like recessive one (Jen et al., 2006). This also true in case of x-linked ataxia and several causative-genes have been reported until now (Apak et al., 1989). Nowadays, exome sequencing is a promising strategy to identify the genetic basis of mendelian disorders of unknown cause especially those suffering from with genetic heterogeneity (Ng et al., 2010). Here, we present a novel deletion in ADCK3 gene in an Iranian family of ARSC.
Several mutations in ADCK3 have been reported in the literature and introduced this gene as one the important gene in pathogenesis of ARSC. 2. Material and methods An Iranian family with three affected boys with symptoms of spinocerebellar atrophy ataxia from consanguineous marriage was included in this study (Fig. 1). The deceased grandfather also had ataxia and died at age 52. He showed the decreased coordination of hands and speech gradually and the MRI was abnormal and showed the cerebellar atrophy. The family did not have more information as several years passed. However, for all three brothers, MRI study was performed through the brain and cerebellar atrophy as sulsal dilation, prominent fulia was evidenced. Poor coordination of hands and walking was also observed in these brothers. Karyotype analysis was normal for all three affected boys. Informed written consent was obtained from the family and the study was ethnically approved by Shahid Chamran University of Ahvaz. The blood
Abbreviations: ARSC, Autosomal recessive cerebellar ataxia; NGS, Next Generation Sequencing; PCR, Polymerase chain reaction; SNP, Single nucleotide Polymorphism; WES, Whole exome sequencing ⁎ Correspondence to: M. Tahmasebi-Birgani, Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences. ⁎⁎ Correspondence to: J. Mohammadi-Asl, Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences and Noor Genetics Lab, Iran. E-mail addresses: [email protected] (M. Tahmasebi-Birgani), [email protected] (J. Mohammadi-asl). https://doi.org/10.1016/j.gene.2019.05.016 Received 23 October 2018; Received in revised form 19 April 2019; Accepted 6 May 2019 Available online 10 May 2019 0378-1119/ © 2019 Published by Elsevier B.V.
Gene 708 (2019) 10–13
M. Hajjari, et al.
Fig. 1. The pedigree of an Iranian family with symptoms of autosomal recessive spinocerebellar ataxia (ARSC). Four patients were clinically diagnosed as ARSC and the individual V-II represents the index patient.
4. Discussion
Table 1 The list of used primers in this study. Primer name
Primer sequence
ADCK3-Forward ADCK3-Reverse
5′-GTGGAGTGGGGGATTCCT-3′ 5′-CCCCTCTAAAGCAGGTCAATC-3′
Here we report a novel mutation in ADCK3 gene in an Iranian family suffering from ARSC using whole exome sequencing. The mutation is pathogenic deletion of amino acids 229–230 of ADCK3 gene which were detected in all affected individuals of the pedigree. The mutation was novel and has been not previously reported in dbSNP or literature. The father carried the mutation and has been probably received it from his father who were diagnosed for cerebellar ataxia too. The human AarF domain containing kinase 3A (ADCK3 or COQ8A) is located on 1q42.13. The gene encodes a membrane protein with electron transfer activity in mitochondrial respiratory chain (Iiizumi et al., 2002). The ADCK3 is one the 13reported genes involved in coenzyme Q (COQ) biosynthesis and cells carrying the mutation in ADCK3, will been countered with significant reduction in their COQ level which eventually disturbed the mitochondrial hemostasis (Cullen et al., 2016). The coenzyme Q is a critical lipophilic factor during oxidative phosphorylation pathway in mitochondria (Iiizumi et al., 2002). It has also demonstrated that expression of human ADCK3can rescue the COQ deficiency symptom in yeast COQ8 mutant model (Xie et al., 2011). The association of ADCK3 gene mutation with recessive ataxia syndrome was firstly described by SNP-array and linkage analysis of a large consanguineous family for childhood-onset recessive ataxia ended to find ADCK3 locus as novel gene of ARSC. The mutation was a donor splice-site c.1398 + 2T > C in intron 11 of ADCK3 gene (Lagier-Tourenne et al., 2008). Consequently, the ADCK3D420Wfs, Q167Lfs, Y514C, T584del, L314_Q369del, G549S, E551K, R213W, G272 V, G272D, N465Dfs, R348X, R348X, L379X, R271C, A304T, A304V, R299W and Y429C mutations reported for childhood, juvenile and adult-onset cases of cerebellar ataxia (Liu et al., 2014). In 2010, Gerards et al. reported two nonsense mutations including c.1136 T > A and c.1042 C > T in ADCK3 in a Dutch family of cerebellar ataxia (Gerards et al., 2010). In overall and until 2014, the association of ADCK3 mutations has been documented in 21 patients from 15 different ethnic groups, all of them showing the manifestation of ataxic cerebellar atrophy (Doimo et al., 2014). In 2014, using WES in an English patient of cerebellar atrophy, Liu et al. found a novel frameshift mutation in ADCK3 p.ser616fs* which leads to extend the protein polypeptide chain by losing the stop codon (Liu et al., 2014). In an
Amplicon size (bp) 500
samples were collected from all affected boys and their available family members and genomic DNA was extracted using salting out protocol. The DNA of one the affected individuals (V-II) were considered for WES analysis (Macrogen, South Korea). The WES-variants were filtered and the pathogenicity of the candidate variant was evaluated using in silico software. Segregation of the mutation through the pedigree was considered by PCR-amplification of DNA around the mutation site using specific primers (Table 1). The PCR amplicon were the sequenced by the same primers and Big Dye Terminators (Applied Bio systems 3130 Genetic Analyzer; Applied Bio systems, Foster City, CA, USA).
3. Results Around 95,572 variants were read in WES. Following the variant calls filtering, an inframe deletion c.685-690 delCTGGCA was found in ADCK3 gene (cDNA.806_811delCTGGCA and g.79943_79948delCTGGCA) of proband (III-VI). The mutation was existed in coding sequence (CDS) of the gene and resulted in deletion Leu229 and Ala 230 (Leu229 Ala 230 del). The candidate variant was novel and was not previously reported elsewhere. In silico analysis predicted the mutation as pathogenic. The variant was near the conserved domain Activator of bc1 complex (ABC1) kinases or aarF domain containing kinase 3 spanning from amino acid 295–545. All the affected brothers (II-2 and II-3) were homozygous for c.685-690 delCTGGCA variant. Although the proband's mother was died, the father was heterozygous for the mutation. Similar to the father, the sister (III-1) was also heterozygous for the candidate variant. The father was carrier of the mutation and has been probably received the mutation from his affected father (Fig. 2).
11
Gene 708 (2019) 10–13
M. Hajjari, et al.
Fig. 2. Sanger sequencing confirmed that ADCK3; del. CD (229–230) variant in all patients of family (a–c). Red and blue boxes show the flanking regions of deletion and deletion site respectively. Evaluation of the presence of WES-extracted pathogenic variant at conserved domain ADCK3 protein (d). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Conflict of interest
American adult-onset cerebellar ataxia patient, Malgireddy and his colleagues reported 2.9 Mb duplication at chromosome region 1q42.11q42.13where the ADCK3 is located (Malgireddy et al., 2017). Similarly, Ozcoraet al. identified the homozygous pathogenic variant p.Ala338Val in ADCK3using whole-exome sequencing in a case of cerebellar ataxia (Ozcora et al., 2017).
The authors declare no conflict of interest. References Apak, S., Yüksel, M., Özmen, M., Saka, N., Darendeliler, F., Neuhäuser, G., 1989. Heterogeneity of X-linked recessive (Spino) cerebellar ataxia with or without spastic diplegia. Am. J. Med. Genet. A 34 (2), 155–158. Cullen, J.K., Murad, N.A., Yeo, A., et al., 2016. Correction: AarF Domain Containing Kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation. PLoS One 11 (7), e0160162. Doimo, M., Desbats, M.A., Cerqua, C., Cassina, M., Trevisson, E., Salviati, L., 2014. Genetics of coenzyme q10 deficiency. Molecular syndromology 5 (3–4), 156–162. Gerards, M., van den Bosch, B., Calis, C., et al., 2010. Nonsense mutations in CABC1/ ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10 (5), 510–515. Iiizumi, M., Arakawa, H., Mori, T., Ando, A., Nakamura, Y., 2002. Isolation of a novel gene, CABC1, encoding a mitochondrial protein that is highly homologous to yeast activity of bc1 complex. Cancer Res. 62 (5), 1246–1250. Jen, J., Lee, H., Cha, Y., Nelson, S., Baloh, R., 2006. Genetic heterogeneity of autosomal dominant nonprogressive congenital ataxia. Neurology 67 (9), 1704–1706. Lagier-Tourenne, C., Tazir, M., López, L.C., et al., 2008. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q 10 deficiency. Am. J. Hum. Genet. 82 (3), 661–672. Liu, Y.T., Hersheson, J., Plagnol, V., et al., 2014. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J. Neurol. Neurosurg. Psychiatry 85 (5), 493–498. Malgireddy, K., Thompson, R., Torres-Russotto, D., 2017. A novel CABC1/ADCK3 mutation in adult-onset cerebellar ataxia (P6. 021). Neurology 88 (16 Supplement) (P6. 021). Ng, S.B., Buckingham, K.J., Lee, C., et al., 2010. Exome sequencing identifies the cause of
5. Conclusion In conclusion, the results of previous study on ADCK3in pathogenesis of cerebellar ataxia as well as the data obtained at this study indicates that ADCK3 and the mutations that occur in it play an important role in the development of this disease. Additionally, if the ataxic patients confirmed for ADCK3 mutation, they can start COQ therapy.
Acknowledgment The authors are contributed to the manuscript as MRH: Data collection and analysis, JMA: Data collection, MTB: Manuscript preparation and data analysis, HN, AK and MH: data collection. All the authors appreciated all friends and colleagues at Noor medical genetics laboratory specially Neda Golchin and Alireza Masbi for their generous assistants. The grant was supported by Shahid Chamran University of Ahvaz (Grant number# 842) and Noor genetic Laboratory, Ahvaz. 12
Gene 708 (2019) 10–13
M. Hajjari, et al.
Wiethoff, S., Hersheson, J., Bettencourt, C., Wood, N.W., Houlden, H., 2016. Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations. J. Neurol. 263 (8), 1503–1510. Xie, L.X., Hsieh, E.J., Watanabe, S., et al., 2011. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1811 (5), 348–360.
a mendelian disorder. Nat. Genet. 42 (1), 30. Ozcora, G.D.K., Basak, N., Canpolat, M., Acer, H., Kumandas, S., 2017. Coenzyme Q10 deficiency; a treatable autosomal recessive cerebellar ataxias. Eur. J. Paediatr. Neurol. 21, e136. Palau, F., Espinós, C., 2006. Autosomal recessive cerebellar ataxias. Orphanet journal of rare diseases 1 (1), 47. Sailer, A., Houlden, H., 2012. Recent advances in the genetics of cerebellar ataxias. Current neurology and neuroscience reports 12 (3), 227–236.
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