• anticipation
• hereditary spastic paraplegias
• multiple ligation‐dependent probe amplification
• whole‐exome sequencing

• Humans
• Spastic Paraplegia, Hereditary/genetics
• Spastic Paraplegia, Hereditary/diagnosis
• Male
• Female
• Adult
• Adolescent
• Young Adult
• Child
• Middle Aged
• Cohort Studies
• Child, Preschool
• Exome Sequencing/methods
• Phenotype
• Genetic Association Studies/methods
• Mutation/genetics
• Aged

• 82371255 National Natural Science Foundation of China
• 82201398 National Natural Science Foundation of China
• 82071258 National Natural Science Foundation of China
• 23XD1402500 Program for Shanghai Outstanding Academic Leaders
• 23DZ2291500 Shanghai Science and Technology Innovation Action Plan
• 2022LJ011 Program for Outstanding Medical Academic Leader of Shanghai
• SHDC2022CRD037 Training program for research physicians of innovative translational ability
• 2022M712117 China Postdoctoral Science Foundation Project
• 22PJD052 Shanghai Pujiang Program
• YNQN202224 Young Scholar Cultivation Project of Basic Scientific Research in Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

• Amyotrophic lateral sclerosis
• Drosophila
• GSK3
• Kinesin
• PP2A

• Animals
• Humans
• Mice
• Amyotrophic Lateral Sclerosis/pathology
• Glycogen Synthase Kinase 3/genetics
• Glycogen Synthase Kinase 3/metabolism
• Protein Phosphatase 2/genetics
• Protein Phosphatase 2/metabolism
• RNA-Binding Protein FUS/genetics
• RNA-Binding Protein FUS/metabolism
• Neurodegenerative Diseases/pathology
• Kinesins/genetics
• Kinesins/metabolism
• Motor Neurons/metabolism
• Drosophila/genetics
• Drosophila/metabolism
• Mutation/genetics

• P40 OD018537 NIH HHS
• Fonds Wetenschappelijk Onderzoek

• spastic paraplegia, hereditary
• movement disorders
• dystonia
• parkinsonian disorders
• tremor
• paraplegia espástica hereditária
• transtornos dos movimentos
• distonia
• transtornos parkinsonianos

• Humans
• Spastic Paraplegia, Hereditary/diagnosis
• Mutation
• Tremor/diagnosis
• Tremor/etiology
• Dystonia/diagnosis
• Dystonia/etiology
• Movement Disorders
• Ataxia
• Parkinsonian Disorders/diagnosis
• Proteins/genetics

• 32230024 National Natural Science Foundation of China (National Science Foundation of China)
• 2021YFA1300800 Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)
• XDB39000000 Bureau of International Cooperation, Chinese Academy of Sciences
• YSBR-075 Bureau of International Cooperation, Chinese Academy of Sciences

• ATL1
• MLPA
• SPAST
• SPG3A
• SPG4
• copy number variation
• multiplex ligation dependent probe amplification
• rearrangements

Portions of the endoplasmic reticulum (ER) are degraded by autophagy (ER-phagy) in response to starvation or the accumulation of misfolded proteins. We show that ER-phagy requires assembly of actin at sites of contact between the edges of ER sheets and endocytic pits on the plasma membrane. Actin assembly may help to bring an element of the ER carrying the selective autophagy receptor Atg40 into the cell interior, where it associates with Atg11, a scaffold needed to recruit components for autophagosome assembly. Understanding the mechanism by which regions of the ER are selected for degradation and sequestered within autophagosomes may help in the development of novel approaches to treat diseases that result from the accumulation of misfolded proteins within the ER.

Fragments of the endoplasmic reticulum (ER) are selectively delivered to the lysosome (mammals) or vacuole (yeast) in response to starvation or the accumulation of misfolded proteins through an autophagic process known as ER-phagy. A screen of the Saccharomyces cerevisiae deletion library identified end3Δ as a candidate knockout strain that is defective in ER-phagy during starvation conditions, but not bulk autophagy. We find that loss of End3 and its stable binding partner Pan1, or inhibition of the Arp2/3 complex that is coupled by the End3-Pan1 complex to endocytic pits, blocks the association of the cortical ER autophagy receptor, Atg40, with the autophagosomal assembly scaffold protein Atg11. The membrane contact site module linking the rim of cortical ER sheets and endocytic pits, consisting of Scs2 or Scs22, Osh2 or Osh3, and Myo3 or Myo5, is also needed for ER-phagy. Both Atg40 and Scs2 are concentrated at the edges of ER sheets and can be cross-linked to each other. Our results are consistent with a model in which actin assembly at sites of contact between the cortical ER and endocytic pits contributes to ER sequestration into autophagosomes.

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 (ATL1), encoding a dynamin superfamily member, which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant prehydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function.

• GTPase
• membrane tethering
• neuropathy
• protein conformation

• SPG12
• SPG17
• SPG31
• SPG6
• SPG8
• SPG9A
• massive parallel sequencing (MPS)
• mutations
• phenotypes
• spastic paraplegias

• Genotype–phenotype associations
• HSP
• Meta-analysis

• Adult
• Genetic Association Studies
• Genotype
• Humans
• Male
• Membrane Transport Proteins/genetics
• Mutation/genetics
• Phenotype
• Proteins/genetics
• Spastic Paraplegia, Hereditary/genetics
• Spastin/genetics

• Japanese
• SPAST
• SPG4
• de novo mutation
• hereditary spastic paraplegia

• Female
• Heterozygote
• Humans
• Japan
• Mutation
• Paraplegia/diagnosis
• Phenotype
• Spastic Paraplegia, Hereditary/diagnosis
• Spastin/genetics
• Young Adult

Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood.

Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP.

Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42^*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families.

Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.

• hereditary spastic paraplegia
• hotspot
• mutation analysis
• receptor expression-enhancing protein 1
• transethnic

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders, it share common symptom - of progressive lower spastic paraparesis. The most common autosomal dominant (AD) forms of HSP are SPG4 (SPAST gene) and SPG3 (ATL1 gene). In the current research we investigated for the first time the distribution of pathogenic mutations in SPAST and ATL1 genes within a large cohort of Russian HSP patients (122 probands; 69 famillial cases). We determined the frequencies of genetic abnormalities using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and Next Generation Sequencing (NGS) of targeted gene panels. As a result, SPG4 was diagnosed in 30.3% (37/122) of HSP cases, where the familial cases represented 37.7% (26/69) of SPG4. In total 31 pathogenic and likely pathogenic variants were detected in SPAST, with 14 new mutations. Among all detected SPAST variants, 29% were gross deletions and duplications. The proportion of SPG3 variants in Russian cohort was 8.2% (10/122) that were all familial cases. All 10 detected ATL1 mutations were missense substitutions, most of which were in the mutational hot spots of 4, 7, 8, 12 exons, with 2 novel mutations. This work will be helpful for the populational genetics of HSP understanding.

• Amyotrophic lateral sclerosis
• Axonal transport
• Neurodegenerative diseases
• Peripheral neuropathy

• Adenosine Triphosphatases/chemistry
• Adenosine Triphosphatases/genetics
• Adenosine Triphosphatases/metabolism
• Adenosine Triphosphatases/ultrastructure
• Allosteric Regulation
• Animals
• Cryoelectron Microscopy
• Drosophila Proteins/chemistry
• Drosophila Proteins/genetics
• Drosophila Proteins/metabolism
• Drosophila Proteins/ultrastructure
• Drosophila melanogaster/genetics
• Drosophila melanogaster/metabolism
• Microtubules/metabolism
• Models, Molecular
• Mutation
• Polyglutamic Acid/metabolism
• Polymerization
• Protein Binding
• Protein Conformation
• Protein Domains
• Structure-Activity Relationship
• Substrate Specificity
• Tubulin/metabolism

• DP2 EB020402 NIBIB NIH HHS
• S10 OD021634 NIH HHS
• Z99 NS999999 Intramural NIH HHS
• ZIA NS003122-03 Intramural NIH HHS

Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations.

A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation.

We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

• Hereditary spastic paraplegia
• SPG3A
• Atlastin-1 (ATL1) gene
• Hearing loss
• Case report

• NGS (Next Generation Sequencing)
• SPG11
• SPG15
• SPG3
• SPG31
• SPG4
• SPG7
• clinical and genetic variability
• hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs’ dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to “traditional workflow/guidelines” by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.

• Ataxia-spasticity
• Hereditary spastic paraplegia
• Movement disorders
• Next-generation sequencing.

• ATL1
• HSP
• SPG3A
• hereditary spastic paraplegia

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.

We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.

Most HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.

Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.

The online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

• ATL1
• Age at onset
• Genotype-phenotype correlation
• Hereditary spastic paraplegia
• Mutation
• SPG3A