Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Mar 12;11(6):981.
doi: 10.3390/cells11060981.

Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Mariana Santos  1 , Joana Damásio  1   2   3 , Susana Carmona  4 , João Luís Neto  1 , Nadia Dehghani  4 , Leonor Correia Guedes  5   6   7 , Clara Barbot  3 , José Barros  2   8 , José Brás  4   9 , Jorge Sequeiros  1   3   8 , Rita Guerreiro  4   9
Affiliations

Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Mariana Santos et al. Cells. .

Abstract

Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.

Keywords: cerebellar ataxia; de novo variant; exome sequencing; molecular mechanisms; recessive ataxia.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Analysis of SPG11 (c.3039-5T > G) (A) and KIF1C (c.1166-2A > G) (B) splice-site variants, with minigene splicing assays. Agarose gel electrophoresis of the transcripts generated by the wild-type (WT) and mutant minigene constructs (on the left): B1 bands (<500 bp) represent transcripts affected by the variants; B2 bands (>500 bp) represent amplified transcripts with intron retention, not affected by the variant. Sanger sequencing of the transcripts corresponding to B1 bands (in the middle). Schematic representation of resulting splicing events (on the right): (A) SPG11 variant creates a new 3′ acceptor splice site, resulting in the retention of 4 nucleotides of intron 16; (B) KIF1C variant abolished the 3′ acceptor splice-site, leading to the usage of a splice site within exon 14 and resulting in the deletion of 8 nucleotides from exon 14. Electropherograms showing the location of the splice-site variants on genomic DNA are shown in Figure S1, supporting information.
Figure 2
Figure 2
Pedigrees of families harboring de novo variants (A), and conservation of the new missense variants and protein models of CACNA1A and ATP1A3 (B). (A) Black symbols represent individuals with cerebellar ataxia. (B) Sequence alignment of the residues surrounding the mutated residues in CACNA1A and ATP1A3 against other species was performed using the Clustal Omega program. Protein models of CACNA1A and ATP1A3 showing altered residues interactions upon amino acid changes (performed using DynaMut2). The Arg1666 and Val135 residues in CACNA1A and ATP1A3, respectively, are in the center, displaying the various interactions with nearby residues in different colors.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Anheim M., Tranchant C., Koenig M. The autosomal recessive cerebellar ataxias. N. Engl. J. Med. 2012;366:636–646. doi: 10.1056/NEJMra1006610. - DOI - PubMed
    1. Ruano L., Melo C., Silva M.C., Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies. Neuroepidemiology. 2014;42:174–183. doi: 10.1159/000358801. - DOI - PubMed
    1. Sequeiros J., Martins S., Silveira I. Epidemiology and population genetics of degenerative ataxias. Handb. Clin. Neurol. 2012;103:227–251. doi: 10.1016/B978-0-444-51892-7.00014-0. - DOI - PubMed
    1. Fogel B.L., Lee H., Deignan J.L., Strom S.P., Kantarci S., Wang X., Quintero-Rivera F., Vilain E., Grody W.W., Perlman S., et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71:1237–1246. doi: 10.1001/jamaneurol.2014.1944. - DOI - PMC - PubMed
    1. van de Warrenburg B.P., Schouten M.I., de Bot S.T., Vermeer S., Meijer R., Pennings M., Gilissen C., Willemsen M.A., Scheffer H., Kamsteeg E.J. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur. J. Hum. Genet. 2016;24:1460–1466. doi: 10.1038/ejhg.2016.42. - DOI - PMC - PubMed

Publication types

Supplementary concepts