Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 i...
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| Format: | Online |
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Public Library of Science
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516553/ |
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pubmed-35165532012-12-12 Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development Lise, Stefano Clarkson, Yvonne Perkins, Emma Kwasniewska, Alexandra Sadighi Akha, Elham Parolin Schnekenberg, Ricardo Suminaite, Daumante Hope, Jilly Baker, Ian Gregory, Lorna Green, Angie Allan, Chris Lamble, Sarah Jayawant, Sandeep Quaghebeur, Gerardine Cader, M. Zameel Hughes, Sarah Armstrong, Richard J. E. Kanapin, Alexander Rimmer, Andrew Lunter, Gerton Mathieson, Iain Cazier, Jean-Baptiste Buck, David Taylor, Jenny C. Bentley, David McVean, Gilean Donnelly, Peter Knight, Samantha J. L. Jackson, Mandy Ragoussis, Jiannis Németh, Andrea H. Research Article β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome. Public Library of Science 2012-12-06 /pmc/articles/PMC3516553/ /pubmed/23236289 http://dx.doi.org/10.1371/journal.pgen.1003074 Text en © 2012 Lise et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Lise, Stefano Clarkson, Yvonne Perkins, Emma Kwasniewska, Alexandra Sadighi Akha, Elham Parolin Schnekenberg, Ricardo Suminaite, Daumante Hope, Jilly Baker, Ian Gregory, Lorna Green, Angie Allan, Chris Lamble, Sarah Jayawant, Sandeep Quaghebeur, Gerardine Cader, M. Zameel Hughes, Sarah Armstrong, Richard J. E. Kanapin, Alexander Rimmer, Andrew Lunter, Gerton Mathieson, Iain Cazier, Jean-Baptiste Buck, David Taylor, Jenny C. Bentley, David McVean, Gilean Donnelly, Peter Knight, Samantha J. L. Jackson, Mandy Ragoussis, Jiannis Németh, Andrea H. |
| spellingShingle |
Lise, Stefano Clarkson, Yvonne Perkins, Emma Kwasniewska, Alexandra Sadighi Akha, Elham Parolin Schnekenberg, Ricardo Suminaite, Daumante Hope, Jilly Baker, Ian Gregory, Lorna Green, Angie Allan, Chris Lamble, Sarah Jayawant, Sandeep Quaghebeur, Gerardine Cader, M. Zameel Hughes, Sarah Armstrong, Richard J. E. Kanapin, Alexander Rimmer, Andrew Lunter, Gerton Mathieson, Iain Cazier, Jean-Baptiste Buck, David Taylor, Jenny C. Bentley, David McVean, Gilean Donnelly, Peter Knight, Samantha J. L. Jackson, Mandy Ragoussis, Jiannis Németh, Andrea H. Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| author_facet |
Lise, Stefano Clarkson, Yvonne Perkins, Emma Kwasniewska, Alexandra Sadighi Akha, Elham Parolin Schnekenberg, Ricardo Suminaite, Daumante Hope, Jilly Baker, Ian Gregory, Lorna Green, Angie Allan, Chris Lamble, Sarah Jayawant, Sandeep Quaghebeur, Gerardine Cader, M. Zameel Hughes, Sarah Armstrong, Richard J. E. Kanapin, Alexander Rimmer, Andrew Lunter, Gerton Mathieson, Iain Cazier, Jean-Baptiste Buck, David Taylor, Jenny C. Bentley, David McVean, Gilean Donnelly, Peter Knight, Samantha J. L. Jackson, Mandy Ragoussis, Jiannis Németh, Andrea H. |
| author_sort |
Lise, Stefano |
| title |
Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| title_short |
Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| title_full |
Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| title_fullStr |
Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| title_full_unstemmed |
Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development |
| title_sort |
recessive mutations in sptbn2 implicate β-iii spectrin in both cognitive and motor development |
| description |
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome. |
| publisher |
Public Library of Science |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516553/ |
| _version_ |
1611938735024242688 |