Suspected new HSP gene SPTAN1

Huge HSP genetics study in Canada

 

The highly regarded HSP research team at McGill University in Montréal Canada have found evidence that the gene SPTAN1 not previously associated with HSP, may be associated with an autosomal recessive form of the condition.

 

They performed genetic analysis of 383 people with HSP from 289 families. Mutations in this gene have previously been associated with another neurodegenerative condition, early infantile epileptic encephalopathy (EIEE5).

 

Abstract

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed.

To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15).

Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans.

This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.

 

SOURCE: J Hum Genet. 2019 Nov;64(11):1145-1151. doi: 10.1038/s10038-019-0669-2. Epub 2019 Sep 12. PMID: 31515523

SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.

Leveille E1, Estiar MA2,3, Krohn L2, Spiegelman D3,4, Dionne-Laporte A3,4, Dupré N5,6, Trempe JF7,8, Rouleau GA9,10,11, Gan-Or Z12,13,14.

1 Faculty of Medicine, McGill University, Montréal, QC, Canada.

2 Department of Human Genetics, McGill University, Montréal, QC, Canada.

3 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.

4 Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.

5 Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada.

6 Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.

7 Department of Pharmacology & Therapeutics, McGill University, Montréal, QC, Canada.

8 Centre for Structural Biology, McGill University, Montréal, QC, Canada.

9 Department of Human Genetics, McGill University, Montréal, QC, Canada. [email protected].

10 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. [email protected].

11 Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. [email protected].

12 Department of Human Genetics, McGill University, Montréal, QC, Canada. [email protected].

13 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. [email protected].

14 Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. [email protected].