A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.
Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in do...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3375262?pdf=render |
| _version_ | 1818315335623770112 |
|---|---|
| author | Kaisa Kyöstilä Sigitas Cizinauskas Eija H Seppälä Esko Suhonen Janis Jeserevics Antti Sukura Pernilla Syrjä Hannes Lohi |
| author_facet | Kaisa Kyöstilä Sigitas Cizinauskas Eija H Seppälä Esko Suhonen Janis Jeserevics Antti Sukura Pernilla Syrjä Hannes Lohi |
| author_sort | Kaisa Kyöstilä |
| collection | DOAJ |
| description | Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw) = 1.1x10(-7), p(genome) = 7.5x10(-4)). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders. |
| first_indexed | 2024-12-13T09:03:54Z |
| format | Article |
| id | doaj.art-0f6fbbe449c849b09e0a88ba4e7b6b69 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T09:03:54Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-0f6fbbe449c849b09e0a88ba4e7b6b692022-12-21T23:53:07ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0186e100275910.1371/journal.pgen.1002759A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.Kaisa KyöstiläSigitas CizinauskasEija H SeppäläEsko SuhonenJanis JeserevicsAntti SukuraPernilla SyrjäHannes LohiInherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw) = 1.1x10(-7), p(genome) = 7.5x10(-4)). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders.http://europepmc.org/articles/PMC3375262?pdf=render |
| spellingShingle | Kaisa Kyöstilä Sigitas Cizinauskas Eija H Seppälä Esko Suhonen Janis Jeserevics Antti Sukura Pernilla Syrjä Hannes Lohi A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. PLoS Genetics |
| title | A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. |
| title_full | A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. |
| title_fullStr | A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. |
| title_full_unstemmed | A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. |
| title_short | A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. |
| title_sort | sel1l mutation links a canine progressive early onset cerebellar ataxia to the endoplasmic reticulum associated protein degradation erad machinery |
| url | http://europepmc.org/articles/PMC3375262?pdf=render |
| work_keys_str_mv | AT kaisakyostila asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT sigitascizinauskas asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT eijahseppala asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT eskosuhonen asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT janisjeserevics asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT anttisukura asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT pernillasyrja asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT hanneslohi asel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT kaisakyostila sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT sigitascizinauskas sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT eijahseppala sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT eskosuhonen sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT janisjeserevics sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT anttisukura sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT pernillasyrja sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery AT hanneslohi sel1lmutationlinksacanineprogressiveearlyonsetcerebellarataxiatotheendoplasmicreticulumassociatedproteindegradationeradmachinery |