Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Biallelic mutations in AP5Z1 are known to cause a rare, autosomal-recessive, complex form of hereditary spastic paraplegia (HSP) referred to as SPG48 (MIM#613647).1 To date, only 11 SPG48 patients have been reported. The clinical spectrum of SPG48 is complex and heterogeneous, presenting with neuropathy, ataxia, dystonia, and parkinsonism in addition to spastic paraplegia (SP). AP5Z1 codes for the ζsubunit of the AP-5 complex, implicated in vesicular-mediated intracellular sorting and trafficking of cargo proteins1 - Functional studies demonstrate the accumulation of multilamellar structures (endolysosomes) in SPG48 skin fibroblasts.2 Here, we screened 2035 HSP patients from 3 tertiary centers (Athens, University of Athens [UOA]; London, University College London; and Paris, Paris, Sciences & Lettres [PSL], Assistance Publique-Hôpitaux de Paris [APHP]) for mutations in AP5Z1 and performed functional studies in 2 cases with pathogenic variants in AP5Z1. We also present a literature review for AP5Z1 cases, a pathway analysis, and follow-up data on previously reported patients, where available (Supplementary Material 1, 4, and 5). In total, 9 patients from 8 unrelated families carrying biallelic pathogenic variants in AP5Z1 were identified (Fig. 1; Supplementary Material 1). We show that AP5Z1-related disease usually presents with a combination of late-onset SP (mean: 54.3 ± 5.3 years) and axonal neuropathy. Other frequent clinical features in our cohort were urinary incontinence, hearing loss, and visual impairment. Interestingly, 1 patient had epileptic seizures. Brain magnetic resonance imaging (MRI) was available for 6 patients. Leukoencephalopathy and thinning of the corpus callosum (TCC) were present in 1 patient and “ears of the lynx” sign, a “moth-eaten” appearance of the basal ganglia, and TCC in another (Fig. 2). The remaining 4 patients had normal MRI. Our extended analysis of all SPG48 patients identified in the literature (Supplementary Material 1) shows that 22 AP5Z1 variants are linked to SPG48 worldwide, including the 8 newly reported here. Follow-up data were obtained from 3 SPG48 patients, all of whom had a disease duration of ≥10 years. The progression of the disease was slow (Supplementary Material 5), with the phenotype consisting of predominantly severe lower-limb spasticity with patients becoming wheelchair-bound after 10 years from onset. AP5Z1 protein levels in patient fibroblasts were reduced to undetectable levels, correlating with an accumulation of lysosomal-associated membrane protein 1 (LAMP1)-positive structures and a 25% deficit in recycling between endosomes and Golgi (Fig. 3, Fig. 4, Supplementary Material 6). This was also supported by functional enrichment analyses which pinpointed that within the network of HSP-associated genes mediating membrane trafficking, AP5Z1 relates to endosomal trafficking, determining the fate of sorting endosomes toward lysosomal fusion, the plasma membrane, or the trans-Golgi network (Supplementary Material 4). In this study we expanded the phenotypic and genotypic spectrum of SPG48 showing that SPG48 is a slowly progressing, late-onset, complicated HSP manifesting with SP, axonal neuropathy, cognitive impairment in line with the SPG48 patients reported so far [and in Refs 1 and 3] and, interestingly, epileptic seizures (patient G, Supplementary Material 3). Epileptic seizures have not been previously reported in SPG48; however, they are well described in other HSP subtypes, such as SPG11 and SPG15, which are functionally related to SPG483 and in many lysosomal storage diseases. Indeed, our functional studies on SPG48 cell lines confirm defects in endosome and lysosome homeostasis. We also confirm here previously described neuroimaging findings (“ears of the lynx” sign, TCC, and white matter lesions) in a subgroup of patients. To date, no specific therapies are approved for HSP. Of note, treatment strategies are proposed in complex forms of HSP such as cholesterol-lowering agents for HSP-CYP7B1 (SPG5A), as CYP7B1 gene is involved in the degradation of cholesterol into primary bile acids.4 A randomized-controlled trial showed that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in the serum of SPG5 patients5 and evolocumab (PCSK9 inhibitor) is currently evaluated in a phase 2 clinical trial (NCT04101643). In addition, “tideglusib” (GSK3β inhibitor) was tested on iPSC neuronal lines of an SPG11 patient and decreased cell death.6 Our study strengthens the evidence supporting autophagic dysfunction as one of the underlying molecular pathways in HSP7 and further expands the phenotypic spectrum of AP5Z1-related SPG48. We thank the participants and their families for their essential help with this work. The Greek family was recruited as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. This work was supported by the Wellcome Trust (Synaptopathies strategic award [104033]), a Wellcome Trust Multi-User Equipment Grant, Muscular Dystrophy UK (MD UK), MDC USA, and the Medical Research Council (MRC UK International Centre and project grants), the French Strumpell-Lorrain association, Spastic Paraplegia Foundation, the MRC (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MD UK), Muscular Dystrophy Association (MDA USA). European Union funding (grant 779257 Solve-RD from the Horizon 2020 Research and Innovation Programme) was provided to G.S. J.H. was supported by grants from the Wellcome Trust: 086598 and 214272 to Microsoft Research Cambridge. G.K. acknowledges support from Genesis Pharma (Grant Number 13044) special account for research grants for the National and Kapodistrian University of Athens. APPENDIX S1. Supplementary Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract Background Tay-Sachs disease (TSD) is a rare autosomalrecessive genetic disorder characterized by progressive destruction of nerve cells in the brain and spinal cord. It is caused by genetic variations in the HEXA gene leading to a deficiency of β hexosaminidase A (HEXA) isoenzyme activity. This study aimed to identify causative gene variants in 3 unrelated consanguineous families presented with TSD from Pakistan and Morocco. Methods Detailed clinical investigations were carried out on probands in 3 unrelated consanguineous families of Pakistani and Moroccan origin. Targeted gene sequencing and Whole Exome Sequencing (WES) were performed for variant identification. Candidate variants were checked for co-segregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP and the 1,000 Genome Project were searched to determine frequencies of the alleles. Conservation of the missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. Results We report on 3 children presented with Tay-Sachs Disease. The β hexosaminidaseA enzyme activity was reduced in the Pakistani patient in one of the pedigrees. Genetic testing revealed 2 novel homozygous variants (p.Asp386Alafs*13 and p.Trp266Gly) in the gene HEXA in Pakistani and Moroccan patients respectively.The third family of Pakistani origin revealed a previously reported variant (p.Tyr427Ilefs*5) in HEXA. p.Tyr427Ilefs*5 is the most commonly occurring pathogenic variationin Ashkenazi but was not reported in Pakistani population. Conclusion Our study further expands the ethnic and mutational spectrum of Tay-Sachs disease emphasizing the usefulness of WES as a powerful diagnostic tool where enzymatic activity is not performed for Tay-Sachs disease. The study recommends targeted screening for these mutations (p.Tyr427Ilefs5) for cost effective testing of TSD patients. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.

Abstract Introduction We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer's disease (AD). Methods We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP‐related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ‐secretase. Results We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ‐secretase reconstitution, it destabilizes γ‐secretase‐amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid‐ring arteries, and severe CAA. Discussion We show that pure SP can precede dementia onset in PSEN1‐related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP‐related genes, particularly when associated with a family history of cognitive decline.

Variants in SETX have been implicated in recessively and dominantly inherited disorders, ataxia with oculomotor apraxia type 2 (AOA2 OMIM# 606002) and amyotrophic lateral sclerosis (ALS4, OMIM# 602433) respectively, in humans. We report two novel bi-allelic pathogenic variants in SETX in patients suffering from ataxia with oculomotor apraxia type 2, extending the allelic spectrum of the gene variants. We also discuss the pathogenicity of SETX variants in relation to the evolutionary conservation status of the affected amino acids. Our analyses suggest that variants of some amino acids which are not fully conserved in evolution, may cause a disorder in humans, provided the particular pathogenic variant is absent in other orthologues.

Background: Several European studies examined the role of C9orf72 repeat expansion in patients with -Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases. Methods: A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson's chi-square statistic for a 2 x 2 table. A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity. Results: In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1-3%) with low heterogeneity (I-2:15%). Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

Bakground: Hereditary Spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of degenerative disorders characterized by progressive spasticity and weakness of the lower limbs. This study aimed to identify causative gene variants in two unrelated consanguineous Pakistani families presented with 2 different forms of HSP. Methods: Whole exome sequencing (WES) was performed in the two families and variants were validated by Sanger sequencing and segregation analysis. Analysis: In family A, a homozygous pathogenic variant in ZFYVE26 was identified in one family. While in family B, a frameshift variant in CYP2U1 was identified in 4 affected individuals presented with clinical features of SPG56. Our study is the first report of ZFYVE26 mutations causing HSP in the Pakistani population and the second report of CYP2U1 in a Pakistani family. Conclusions: Our findings enhance the clinical and genetic variability associated with two rare autosomal recessive HSP genes, highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Emerging data have established links between paroxysmal neurological disorders or psychiatric disorder, such as migraine, ataxia, movement disorders and epilepsy. Common gene signatures such as expression, protein interaction and the associated signalling pathways link genes in these associated disorders, with the object to predict unknown disease or risk genes. In this study, we used gene interaction networks to investigate common gene signatures associated with the above phenotypes. In total, 19 candidate genes were used for making an interaction network which further revealed 39 associated genes (including KCNA1, SCN2A, CACNA1A, KCNM4, KCNO3, SCN1B and CACNB4) implicated in paroxysmal neurological disorders development and progression. The meta-regression analysis showed the strongest association of SCN2A with genes involved in schizophrenia and neurodevelopmental disorders. Importantly, our analysis showed KCNMA1 as a common gene signature with a link to epilepsy, movement disorders and wide paroxysmal neurological presentations—with the greatest potential risk of being a disease gene in a paroxysmal or psychiatric disorder. Further gene interaction analysis is required to identify unidentified gene interactions which may be targets for future drugs development.

A total of 178 consecutive patients with definite sALS without frontotemporal dementia (FTD) were enrolled in this study, after complete clinical evaluation. A Repeat-Primed Polymerase Chain Reaction (RP-PCR) protocol was applied to detect the G4C2 repeats expansions. In the studied sALS patients, 5.06% (n = 9) carried the C9orf72 mutation. Among carriers, 2/3 of them were females and spinal onset accounted for 78% and bulbar for 22%, while the mean age of onset was about 60 years. Our study showed that the prevalence of C9orf72 repeat expansion in Greek sALS patients is similar to the overall frequency of the mutation in European populations. The pathogenic mutation remains a promising biomarker for genetic testing and targeted treatment.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

Background: The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined. Methods: A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed. Results and Discussion: In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD-phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72-related neurodegeneration that could explain the wide phenotypic variation.

Background: Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients. Methods: We investigated a Greek HSP family using whole exome sequencing (WES). Results: A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI. Conclusions: We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.