DNAJC13 mutations in Parkinson disease

Carles Vilariño-Güell, Alex Rajput, Austen J. Milnerwood, Brinda Shah, Chelsea Szu-Tu, Joanne Trinh, Irene Yu, Mary Encarnacion, Lise N. Munsie, Lucia Tapia, Emil K. Gustavsson, Patrick Chou, Igor Tatarnikov, Daniel M. Evans, Frederick T. Pishotta, Mattia Volta, Dayne Beccano-Kelly, Christina Thompson, Michelle K. Lin, Holly E. ShermanHeather J. Han, Bruce L. Guenther, Wyeth W. Wasserman, Virginie Bernard, Colin J. Ross, Silke Appel-Cresswell, A. Jon Stoessl, Christopher A. Robinson, Dennis W Dickson, Owen A Ross, Zbigniew K Wszolek, Jan O. Aasly, Ruey Meei Wu, Faycal Hentati, Rachel A. Gibson, Peter S. McPherson, Martine Girard, Michele Rajput, Ali H. Rajput, Matthew J. Farrer

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

Original languageEnglish (US)
Pages (from-to)1794-1801
Number of pages8
JournalHuman Molecular Genetics
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2014
Externally publishedYes

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Parkinson Disease
Mutation
Lewy Bodies
Parkinsonian Disorders
Endocytosis
Pathology
Saskatchewan
Exome
Tunisia
Clathrin
Poisons
Endosomes
Exocytosis
Recycling
Norway
Ecology
Taiwan
Haplotypes
Canada
Genome

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vilariño-Güell, C., Rajput, A., Milnerwood, A. J., Shah, B., Szu-Tu, C., Trinh, J., ... Farrer, M. J. (2014). DNAJC13 mutations in Parkinson disease. Human Molecular Genetics, 23(7), 1794-1801. https://doi.org/10.1093/hmg/ddt570

DNAJC13 mutations in Parkinson disease. / Vilariño-Güell, Carles; Rajput, Alex; Milnerwood, Austen J.; Shah, Brinda; Szu-Tu, Chelsea; Trinh, Joanne; Yu, Irene; Encarnacion, Mary; Munsie, Lise N.; Tapia, Lucia; Gustavsson, Emil K.; Chou, Patrick; Tatarnikov, Igor; Evans, Daniel M.; Pishotta, Frederick T.; Volta, Mattia; Beccano-Kelly, Dayne; Thompson, Christina; Lin, Michelle K.; Sherman, Holly E.; Han, Heather J.; Guenther, Bruce L.; Wasserman, Wyeth W.; Bernard, Virginie; Ross, Colin J.; Appel-Cresswell, Silke; Stoessl, A. Jon; Robinson, Christopher A.; Dickson, Dennis W; Ross, Owen A; Wszolek, Zbigniew K; Aasly, Jan O.; Wu, Ruey Meei; Hentati, Faycal; Gibson, Rachel A.; McPherson, Peter S.; Girard, Martine; Rajput, Michele; Rajput, Ali H.; Farrer, Matthew J.

In: Human Molecular Genetics, Vol. 23, No. 7, 01.04.2014, p. 1794-1801.

Research output: Contribution to journalArticle

Vilariño-Güell, C, Rajput, A, Milnerwood, AJ, Shah, B, Szu-Tu, C, Trinh, J, Yu, I, Encarnacion, M, Munsie, LN, Tapia, L, Gustavsson, EK, Chou, P, Tatarnikov, I, Evans, DM, Pishotta, FT, Volta, M, Beccano-Kelly, D, Thompson, C, Lin, MK, Sherman, HE, Han, HJ, Guenther, BL, Wasserman, WW, Bernard, V, Ross, CJ, Appel-Cresswell, S, Stoessl, AJ, Robinson, CA, Dickson, DW, Ross, OA, Wszolek, ZK, Aasly, JO, Wu, RM, Hentati, F, Gibson, RA, McPherson, PS, Girard, M, Rajput, M, Rajput, AH & Farrer, MJ 2014, 'DNAJC13 mutations in Parkinson disease', Human Molecular Genetics, vol. 23, no. 7, pp. 1794-1801. https://doi.org/10.1093/hmg/ddt570
Vilariño-Güell C, Rajput A, Milnerwood AJ, Shah B, Szu-Tu C, Trinh J et al. DNAJC13 mutations in Parkinson disease. Human Molecular Genetics. 2014 Apr 1;23(7):1794-1801. https://doi.org/10.1093/hmg/ddt570
Vilariño-Güell, Carles ; Rajput, Alex ; Milnerwood, Austen J. ; Shah, Brinda ; Szu-Tu, Chelsea ; Trinh, Joanne ; Yu, Irene ; Encarnacion, Mary ; Munsie, Lise N. ; Tapia, Lucia ; Gustavsson, Emil K. ; Chou, Patrick ; Tatarnikov, Igor ; Evans, Daniel M. ; Pishotta, Frederick T. ; Volta, Mattia ; Beccano-Kelly, Dayne ; Thompson, Christina ; Lin, Michelle K. ; Sherman, Holly E. ; Han, Heather J. ; Guenther, Bruce L. ; Wasserman, Wyeth W. ; Bernard, Virginie ; Ross, Colin J. ; Appel-Cresswell, Silke ; Stoessl, A. Jon ; Robinson, Christopher A. ; Dickson, Dennis W ; Ross, Owen A ; Wszolek, Zbigniew K ; Aasly, Jan O. ; Wu, Ruey Meei ; Hentati, Faycal ; Gibson, Rachel A. ; McPherson, Peter S. ; Girard, Martine ; Rajput, Michele ; Rajput, Ali H. ; Farrer, Matthew J. / DNAJC13 mutations in Parkinson disease. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 7. pp. 1794-1801.
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abstract = "A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.",
author = "Carles Vilari{\~n}o-G{\"u}ell and Alex Rajput and Milnerwood, {Austen J.} and Brinda Shah and Chelsea Szu-Tu and Joanne Trinh and Irene Yu and Mary Encarnacion and Munsie, {Lise N.} and Lucia Tapia and Gustavsson, {Emil K.} and Patrick Chou and Igor Tatarnikov and Evans, {Daniel M.} and Pishotta, {Frederick T.} and Mattia Volta and Dayne Beccano-Kelly and Christina Thompson and Lin, {Michelle K.} and Sherman, {Holly E.} and Han, {Heather J.} and Guenther, {Bruce L.} and Wasserman, {Wyeth W.} and Virginie Bernard and Ross, {Colin J.} and Silke Appel-Cresswell and Stoessl, {A. Jon} and Robinson, {Christopher A.} and Dickson, {Dennis W} and Ross, {Owen A} and Wszolek, {Zbigniew K} and Aasly, {Jan O.} and Wu, {Ruey Meei} and Faycal Hentati and Gibson, {Rachel A.} and McPherson, {Peter S.} and Martine Girard and Michele Rajput and Rajput, {Ali H.} and Farrer, {Matthew J.}",
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AU - Vilariño-Güell, Carles

AU - Rajput, Alex

AU - Milnerwood, Austen J.

AU - Shah, Brinda

AU - Szu-Tu, Chelsea

AU - Trinh, Joanne

AU - Yu, Irene

AU - Encarnacion, Mary

AU - Munsie, Lise N.

AU - Tapia, Lucia

AU - Gustavsson, Emil K.

AU - Chou, Patrick

AU - Tatarnikov, Igor

AU - Evans, Daniel M.

AU - Pishotta, Frederick T.

AU - Volta, Mattia

AU - Beccano-Kelly, Dayne

AU - Thompson, Christina

AU - Lin, Michelle K.

AU - Sherman, Holly E.

AU - Han, Heather J.

AU - Guenther, Bruce L.

AU - Wasserman, Wyeth W.

AU - Bernard, Virginie

AU - Ross, Colin J.

AU - Appel-Cresswell, Silke

AU - Stoessl, A. Jon

AU - Robinson, Christopher A.

AU - Dickson, Dennis W

AU - Ross, Owen A

AU - Wszolek, Zbigniew K

AU - Aasly, Jan O.

AU - Wu, Ruey Meei

AU - Hentati, Faycal

AU - Gibson, Rachel A.

AU - McPherson, Peter S.

AU - Girard, Martine

AU - Rajput, Michele

AU - Rajput, Ali H.

AU - Farrer, Matthew J.

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