Exome sequencing reveals two FA2H mutations in a family with a complicated form of Hereditary Spastic Paraplegia and psychiatric impairments

Abstract Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

Download Full-text

A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

10.21203/rs.3.rs-26296/v1 ◽

2020 ◽

Author(s):

Weiwei Yu ◽

Haiqiang Jin ◽

Jianwen Deng ◽

Ding Nan ◽

Yining Huang

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Spastic Paraplegia ◽

Dna Isolation ◽

Tertiary Structure ◽

Novel Mutation ◽

Chinese Family ◽

Spastic Paraplegia ◽

Whole Exome ◽

And Function

Abstract Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and the this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

Download Full-text

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia

Neurology Genetics ◽

10.1212/nxg.0000000000000514 ◽

2020 ◽

Vol 6 (5) ◽

pp. e514

Author(s):

Yasuko Odake ◽

Kishin Koh ◽

Yoshihisa Takiyama ◽

Hiroyuki Ishiura ◽

Shoji Tsuji ◽

...

Keyword(s):

Intellectual Disability ◽

Sequence Analysis ◽

Hereditary Spastic Paraplegia ◽

Psychiatric Symptoms ◽

Spastic Paraparesis ◽

Spastic Paraplegia ◽

Caudate Nuclei ◽

Extrapyramidal Signs ◽

Complicated Form ◽

Exome Sequence

ObjectiveTo establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).MethodsPhysical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.ResultsThe 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.ConclusionsOur study further broadens the clinical spectrum associated with ATP13A2 mutations.

Download Full-text

CAPN1 mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype

Practical Neurology ◽

10.1136/practneurol-2017-001842 ◽

2018 ◽

Vol 18 (5) ◽

pp. 369-372 ◽

Cited By ~ 7

Author(s):

Jeffrey Lambe ◽

Bernadette Monaghan ◽

Tudor Munteanu ◽

Janice Redmond

Keyword(s):

Exome Sequencing ◽

Spinocerebellar Ataxia ◽

Hereditary Spastic Paraplegia ◽

Diagnostic Testing ◽

Next Generation ◽

Spastic Paraplegia ◽

Sequencing Technologies ◽

Disease Entities ◽

Mixed Phenotype ◽

Generation Sequencing

Increasing availability of next-generation sequencing technologies has revealed several limitations of diagnosis-driven traditional clinicogenetic disease classifications, particularly among patients with an atypical or mixed phenotype. Hereditary spastic paraplegia (HSP) and spinocerebellar ataxia (SCA) are two such disease entities with an often overlapping presentation, in which next generation exome sequencing has played a key role in identification of genes causing disease along a continuum of ataxia and spasticity. We describe a patient who presented with features of both ataxia and spasticity, in whom initial diagnostic testing was inconclusive. Ultimately next generation exome sequencing identified homozygosity for a pathogenic variant in exon 13 of the CAPN1 gene c.1534C>T(p.Arg512Cys). This case supports consideration of a less discriminatory classification system among such patients, potentially allowing for more expedient diagnosis through testing of a larger gene panel along the ‘ataxia-spasticity spectrum’.

Download Full-text