SPG4 Founder Effect in French Canadians with Hereditary Spastic Paraplegia

Background:The most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) is mutations in the SPG4 gene. We have previously identified novel SPG4 mutations in a collection of North American families including the c.G1801A mutation present in two families from Quebec. The aim of this study is to estimate the frequency of the c.G1801A mutation in the French Canadian (FC) population and to determine whether this mutation originates from a common ancestor.Methods:We collected and sequenced exon 15 in probands of 37 families. Genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families. Clinical information was reviewed by a neurologist with expertise in HSP.Results:We have identified three additional unrelated families with the c.G1801A mutation and haplotype analysis revealed that all five families share a common ancestor. The mutation is present in 7% of all our FC families and explains half of our spastin linked FC families. The phenotype associated with the c.G1801A genotype is pure HSP with bladder involvement.Conclusion:In this study we have determined that the relative frequency of the c.G1801A mutation in our FC collection is 7%, and approximately 50% in the spastin positive FC group. This mutation is the most common HSP mutation identified in this population to date and is suggestive of a founder effect in Quebec.

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A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

Human Genome Variation ◽

10.1038/s41439-021-00153-x ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Takuya Morikawa ◽

Shiroh Miura ◽

Takahisa Tateishi ◽

Kazuhito Noda ◽

Hiroki Shibata

Keyword(s):

Molecular Diagnosis ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Family Members ◽

Pathogenic Variant ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Nonsynonymous Variant ◽

Japanese Family ◽

Functional Variants

AbstractSpastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

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Mutation analysis of thespastingene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia

Human Mutation ◽

10.1002/humu.10105 ◽

2002 ◽

Vol 20 (2) ◽

pp. 127-132 ◽

Cited By ~ 70

Author(s):

S. Sauter ◽

B. Miterski ◽

S. Klimpe ◽

D. Bönsch ◽

L. Schöls ◽

...

Keyword(s):

Mutation Analysis ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Spastic Paraplegia

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Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1

Neurogenetics ◽

10.1007/s10048-020-00608-3 ◽

2020 ◽

Vol 21 (3) ◽

pp. 169-177

Author(s):

Jianda Wang ◽

Yanqi Hou ◽

Lina Qi ◽

Shuang Zhai ◽

Liangwu Zheng ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Spastic Paraplegia

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Review for "Corpus callosum thinning in autosomal dominant hereditary spastic paraplegia associated with a novel TUBβ4A mutation"

10.1111/cge.13809/v1/review1 ◽

2020 ◽

Author(s):

Alessio Di Fonzo

Keyword(s):

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Spastic Paraplegia

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Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia

Brain ◽

10.1093/brain/awz158 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2238-2252 ◽

Cited By ~ 5

Author(s):

Xiang Lin ◽

Hui-Zhen Su ◽

En-Lin Dong ◽

Xiao-Hong Lin ◽

Miao Zhao ◽

...

Keyword(s):

Exome Sequencing ◽

Cortical Neurons ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Wild Type Mouse ◽

Spastic Paraplegia ◽

Endosomal Sorting ◽

Hereditary Spastic Paraplegias ◽

Cultured Cortical Neurons

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.

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