Novel mutations in the sacsin gene in ataxia patients from Maritime Canada
Introduction
Inherited ataxias represent a large family of genetic disorders with considerable heterogeneity [1], [2]. As a result, the molecular characterization of new patients and families with putative genetic ataxia remains challenging. Among ataxias already genetically characterized, there are significant overlaps in clinical phenotype (spinocerebellar ataxias include more than ten identified genes). Individual genes may mutate to cause subtly or severely different clinical presentations. Moreover, patients may be ascertained at various points in their lifetime, making studies of disease progression for diagnostic purposes problematic.
Ultimately, despite the best efforts of clinical investigators to classify and subclassify such well ascertained conditions, molecular characterization increasingly provides a critical diagnostic criterion. Such characterization often involves sequencing of genes previously reported to mutate to a given clinical condition; however in some situations where the total number of known genes for a condition is prohibitive, or if some aspects of clinical presentation are atypical, or if a causal mutation is atypical and difficult to identify by coding exon resequencing, full genome analysis may be a more efficient technical approach. In the current report, we present a molecular genetic analysis of two families from Maritime Canada, ascertained for ataxia. Although genetic studies performed in the purely clinical context suggested that the underlying molecular basis of the condition might be novel in these families, we have now shown that they result from mutations in the sacsin gene (HGNC symbol SACS). Our experience documents the comparable efficiency of whole genome analysis versus candidate gene approaches for molecular diagnosis when families are available, and expands the genotype phenotype correlation for mutations in sacsin.
Section snippets
Clinical ascertainment and consent
Patients were identified in the course of routine clinical ascertainment and treatment of movement disorders in the neurology clinic at the IWK Health Centre. Approval for the research study was obtained from the IWK research ethics board. All sampled family members provided informed consent to participate in the study. DNA was obtained from blood samples using routine extraction methods. All procedures were in accordance with ethical and methodological standards for human experimentation.
Genotyping and analysis
Whole
Clinical ascertainment
Among our collection of patients and families with various types of ataxia, two families were noted with a similar particular clinical presentation (Fig. 1, Table 1). The patients were all seen as adults. All affected patients had ataxia, dysarthria and pes cavus. All exhibited nystagmus, although this was not a prominent finding. Four of the six patients had a Babinski sign. Family 1 patients had hyperreflexia and more severe spasticity than those in family 2, however these examinations were
Discussion
We report the identification of two novel mutations in the sacsin gene in Acadian Canadian families segregating an autosomal recessive form of ataxia. Although numerous mutations have been reported in sacsin, recently reviewed [14], it was not an immediately obvious candidate gene due to clinical differences in presentation from the most common form of mutated sacsin, clinically termed ARSACS [15]. Moreover there are many different monogenic syndromes molecularly characterized to date in the
Acknowledgements
We are grateful to the family members who generously contributed their time and materials for this research. The following agencies provided funding for this project: Genome Canada, Genome Atlantic, Nova Scotia Health Research Foundation, Nova Scotia Research and Innovation Trust, IWK Health Centre Foundation, and Capital Health Research Fund.
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2020, Journal of the Neurological SciencesCitation Excerpt :Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a paediatric-onset slowly progressive neurological disease characterized by cerebellar, pyramidal, and neuropathic signs. It is the second most prevalent recessive ataxia in the Netherlands, Germany and UK, and cases have been described in 23 countries [1–19]. The cardinal symptom of ARSACS is gait ataxia [20].
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2018, Journal of Biological ChemistryCitation Excerpt :The amino acid sequence of sacsin supports the hypothesis of a quality control function, but more studies are needed. Sr1 is a site for a number of disease-causing mutations: D168Y (23), T201K (24), R272C (25), R272H (19), and L308F (26). How these mutations contribute to ARSACS is unclear in the absence of structural information.
Spastic ataxias
2018, Handbook of Clinical NeurologyCitation Excerpt :An increasing number of atypical cases, including some with no ataxia, no spasticity, autonomic dysfunction, hearing loss, and neuropsychiatric disorders, result in wide clinical heterogeneity in ARSACS. The latter is due to a number of novel ARSACS mutations recently detected with whole-gene exome sequencing (Breckpot et al., 2008; Kamada et al., 2008; McMillan et al., 2009; Guernsey et al., 2010). Most ARSACS patients with hearing loss present with large-scale SACS deletions and nonsense mutations (Terracciano et al., 2009).
Autosomal recessive spastic ataxia of Charlevoix-Saguenay: An overview
2011, Parkinsonism and Related DisordersCitation Excerpt :A recent study demonstrated that sacsin may interact with the Hsp70 chaperone machinery, which is an important component of the cellular response towards aggregation prone mutant proteins that are associated with neurodegenerative diseases [9]. Since the identification of several other mutations in many populations, it is now recognized that ARSACS is not only limited to this region but occurs worldwide [7,10–30]. Furthermore, Clinical variations such as mental retardation, later onset, ophthalmoplegia, hyperlipidemia and absence of spasticity and retinal hypermyelination, have been widely reported in non-Quebec patients [7,10–30].
Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4
2010, American Journal of Human GeneticsCitation Excerpt :Such individuals presumably arise from a more prevalent deleterious mutation, rising to moderately increased frequency through an early founder effect, combining with a second mutation arising more recently and thus found only in the heterozygous state. We similarly identified two different mutations in the sacsin gene (SACS [MIM 604490]) in two Maritime Canadian ataxia families, in which one family was homozygous and the other compound heterozygous for the same mutation plus a different second mutation.46 Our three patients studied showed overall phenotypic similarity, including severe microcephaly from birth and absence of other dysmorphic features.
A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases
2020, Journal of Molecular Neuroscience