Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion.

Authors:
Rossella Spataro
Rossella Spataro
University of Palermo
Italy
Maria Kousi
Maria Kousi
Center for Human Disease Modeling
Finland
Jason R Willer
Jason R Willer
Center for Human Disease Modeling
Jay P Ross
Jay P Ross
University of British Columbia
Canada
Patrick A Dion
Patrick A Dion
Université de Montréal
Canada
Guy A Rouleau
Guy A Rouleau
Montreal Neurological Institute
Montréal | Canada
Mark J Daly
Mark J Daly
Massachusetts General Hospital
Boston | United States

Hum Genomics 2019 Apr 16;13(1):19. Epub 2019 Apr 16.

Center for Human Disease Modeling, Duke University Medical Center, Carmichael Building, 300 North Duke Street, Suite 48-118, Durham, NC, 27701, USA.

Background: Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.

Results: We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study.

Conclusions: We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.

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http://dx.doi.org/10.1186/s40246-019-0203-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469102PMC
April 2019
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References

(Supplied by CrossRef)
Article in Genome Biol
R Shaheen et al.
Genome Biol 2016
Article in Exp Neurobiol
T Lopes da Fonseca et al.
Exp Neurobiol 2014
Article in Cell Cycle
S Martin et al.
Cell Cycle 2015
Article in Biochem Biophys Res Commun
PJ Schultheis et al.
Biochem Biophys Res Commun 2004
Article in Acta Neurol Scand
AS Najim al-Din et al.
Acta Neurol Scand 1994
Article in Nat Genet
A Ramirez et al.
Nat Genet 2006
Article in Mov Disord
MI Behrens et al.
Mov Disord 2010
Article in Acta Neurol Taiwanica
HJ Lai et al.
Acta Neurol Taiwanica 2012
Article in Neurogenetics
L Santoro et al.
Neurogenetics 2011
Article in Hum Mol Genet
J Bras et al.
Hum Mol Genet 2012
Article in Acta Neuropathol
FM Tome et al.
Acta Neuropathol 1985

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