DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability
Introduction
Parkinson's disease (PD) is characterized by resting tremor, muscular rigidity, bradykinesia, postural instability, and response to L-Dopa. Juvenile parkinsonism is described as parkinsonism with an age of onset <21 years. It is a rare and heterogeneous syndrome that can present with a clinical picture similar to idiopathic PD or manifest with additional signs, such as dystonia, cognitive impairment, neurobehavioral abnormalities, pyramidal disturbances, ophthalmoparesis, and autonomic dysfunction [1]. Recessive mutations have been identified in several genes associated with juvenile or young onset parkinsonism [2], [3], [4], [5], [6], [7], three of which are responsible for clinical phenotypes that are almost indistinguishable from sporadic PD: PARK2 (MIM 602544), which encodes parkin; PINK1 (MIM 608309), which is responsible for PARK6; DJ1 (MIM 602533), which is responsible for PARK7. Mutations in PARK2 have been implicated in about half of patients with autosomal recessive early onset parkinsonism [2]. Mutations in ATP13A2 (MIM 610513), responsible for PARK9 or Kufor-Rakeb syndrome, have been identified in patients with early onset parkinsonism, ophthalmoparesis, myoclonic jerks, pyramidal tract signs, and dementia [6], [7]. PARK15 is a parkinsonian-pyramidal syndrome caused by FBXO7 mutation (MIM 605648) and characterized by L-Dopa responsiveness, hyperreflexia, spasticity, dystonic posture, and normal mental status [5]. Other genes associated with similar clinical phenotypes include PLA2G6 (MIM 603604) and SPATACSIN (SPG11; MIM 610844) [7].
Recently a homozygous splicing DNAJC6 mutation was reported in two brothers with juvenile parkinsonism, via autozygosity analysis and exome sequencing [8]. Also, a homozygous 80-kb deletion that encompassed part of DNAJC6 and part of LEPR (leptin receptor) was identified by oligonucleotide array-CGH in a boy having obesity, epilepsy and mental retardation but not any signs of parkinsonism, and the phenotype of the DNAJC6 defect was suggested as mental retardation and/or epilepsy [9].
DNAJC6 (DNAJ/HSP40 homolog, subfamily C member 6; MIM 608375) encodes auxilin, which was originally identified as a clathrin-associated protein that was neuron-specific and enriched in nerve terminals, suggesting that it may play a role in synaptic vesicle recycling [10]. Auxilin is the co-chaperone that recruits HSC70 to the clathrin coated vesicles (CCVs) for disassembly [11], [12], [13], [14], [15], [16], [17]. Defective auxilin causing parkinsonism is in line with parkinsonism often being an endosomal disorder commonly related to CCVs and synaptic vesicle recycling. An association between SNP rs11248051 in GAK (another co-chaperone of HSC70 with 50% amino acid identity to auxilin) and late onset PD has been reported [18]. Alpha-synuclein (MIM 163890), which is associated with autosomal dominant PARK1, also has a role in clathrin-mediated endocytosis and is specifically involved in synaptic vesicle recycling [19]. Another dominant gene that plays a role in endosomal trafficking is VPS35, responsible for late onset PD [20], [21]. The protein product mediates transport between endosomes and the trans-Golgi network [22].
Herein we report clinical findings in four related patients afflicted with progressive juvenile parkinsonism, the mapping of the disease gene by linkage analysis and homozygosity mapping, and the identification of a homozygous nonsense mutation in DNAJC6 by exome sequencing analysis. The phenotypes of our patients resemble those of the patients from the two previously reported families, which among themselves seem not to share any clinical features.
Section snippets
The family
The family was highly consanguineous and from an inbred village. Nine unaffected family members and the four affected members were included in the study (Fig. 1). The Boğaziçi University Institutional Review Board for Research with Human Participants approved the study protocol, and informed consent was obtained from/for all participants.
Genotyping and statistical analysis
DNA was extracted from peripheral blood samples using a standard protocol, and samples from all family members that participated in the study were subjected to
Clinical findings
The patients were examined for the first time at ages 13–22 years. They had similar clinical phenotypes, with mild to moderate mental retardation (IQ:40–63, as assessed by WISC-R test), postural instability, resting and postural tremor, bradykinesia, rigidity, intermittent dystonic symptoms and pyramidal signs. Three patients had absence and generalized seizures that started at the age of 1–5 years, which were controlled with valproic acid. Response to L-Dopa (62.5 mg) was good but limited by
Discussion
The disease in our patients was similar to others that are due to recessive mutations in ATP13A2, FBXO7, PLA2G6 and SPATACSIN, with respect to early onset parkinsonian-pyramidal phenotype and L-Dopa response. Cognitive impairment is a common feature in patients with mutations in these genes, with the exception of some patients with particular FBXO7 mutations. We found that our patients had mental retardation. In contrast to most patients with mutations in these genes, our patients did not have
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We thank the family for participating in the study. We gratefully acknowledge the microsatellite genome scan performed by NHLBI Mammalian Genotyping Service (Contract Number HV48141). This work was supported by Boğaziçi University Research Fund (5708 and 5186).
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