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A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.

Kyöstilä K, Cizinauskas S, Seppälä EH, Suhonen E, Jeserevics J, Sukura A, Syrjä P, Lohi H - PLoS Genet. (2012)

Bottom Line: Pathological and histological examinations indicated cerebellum-restricted neurodegeneration.The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort.Furthermore, our results have enabled the development of a genetic test for breeders.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

ABSTRACT
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.

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Genetic studies.(A) A Manhattan plot of case-control genome-wide association test performed using 13 cases and 7 unaffected sibling-controls. (B) Results of the family-based testing on the disease associated chromosome 8. Plotted are single-point linkage analysis LOD scores, association test p-values and joint analysis p-values. (C) Genotypes at the disease associated locus on CFA8. All cases share a 1.5 Mb homozygous block, and within this block BICF2P948919 shows complete segregation with the disease. (D) A schematic representation of the seven genes found on the 1.5 Mb block and of the SEL1L gene structure. SEL1L exons are marked with black boxes and red denotes the untranslated regions (UTRs). BICF2P948919 is located on second SEL1L intron and the c.1972T>C mutation on exon 19. (E) Chromatograms of the c.1972T>C mutation in an affected, a carrier and a wild-type dog.
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pgen-1002759-g004: Genetic studies.(A) A Manhattan plot of case-control genome-wide association test performed using 13 cases and 7 unaffected sibling-controls. (B) Results of the family-based testing on the disease associated chromosome 8. Plotted are single-point linkage analysis LOD scores, association test p-values and joint analysis p-values. (C) Genotypes at the disease associated locus on CFA8. All cases share a 1.5 Mb homozygous block, and within this block BICF2P948919 shows complete segregation with the disease. (D) A schematic representation of the seven genes found on the 1.5 Mb block and of the SEL1L gene structure. SEL1L exons are marked with black boxes and red denotes the untranslated regions (UTRs). BICF2P948919 is located on second SEL1L intron and the c.1972T>C mutation on exon 19. (E) Chromatograms of the c.1972T>C mutation in an affected, a carrier and a wild-type dog.

Mentions: We subsequently proceeded to map the FH ataxia locus by using a genome-wide approach. A cohort of 31 dogs, comprising 13 cases, 11 obligate carrier parents and seven non-affected siblings, were genotyped using Illumina's 22K canine SNP chip. A standard case-control association test was carried out on the 13 cases and seven full-sibling controls by using PLINK software [36]. This revealed a genome-wide significant association on CFA8 with two SNPs, BICF2P948919 and BICF2P754995, that had the best nominal and corrected p-values of praw = 1.1×10−7 and pgenome = 7.5×10−4 (Figure 4A). The association results were confirmed by utilizing a joint family-based linkage and association analysis program PSEUDOMARKER [37]. The joint analysis, which was carried out on the associated CFA8 using the entire genotyped sample cohort, identified the same locus and a single most significant SNP, BICF2P948919 (LOD score = 3.3, association p = 2.2×10−7 and joint analysis p = 4.0×10−10) (Figure 4B).


A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.

Kyöstilä K, Cizinauskas S, Seppälä EH, Suhonen E, Jeserevics J, Sukura A, Syrjä P, Lohi H - PLoS Genet. (2012)

Genetic studies.(A) A Manhattan plot of case-control genome-wide association test performed using 13 cases and 7 unaffected sibling-controls. (B) Results of the family-based testing on the disease associated chromosome 8. Plotted are single-point linkage analysis LOD scores, association test p-values and joint analysis p-values. (C) Genotypes at the disease associated locus on CFA8. All cases share a 1.5 Mb homozygous block, and within this block BICF2P948919 shows complete segregation with the disease. (D) A schematic representation of the seven genes found on the 1.5 Mb block and of the SEL1L gene structure. SEL1L exons are marked with black boxes and red denotes the untranslated regions (UTRs). BICF2P948919 is located on second SEL1L intron and the c.1972T>C mutation on exon 19. (E) Chromatograms of the c.1972T>C mutation in an affected, a carrier and a wild-type dog.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375262&req=5

pgen-1002759-g004: Genetic studies.(A) A Manhattan plot of case-control genome-wide association test performed using 13 cases and 7 unaffected sibling-controls. (B) Results of the family-based testing on the disease associated chromosome 8. Plotted are single-point linkage analysis LOD scores, association test p-values and joint analysis p-values. (C) Genotypes at the disease associated locus on CFA8. All cases share a 1.5 Mb homozygous block, and within this block BICF2P948919 shows complete segregation with the disease. (D) A schematic representation of the seven genes found on the 1.5 Mb block and of the SEL1L gene structure. SEL1L exons are marked with black boxes and red denotes the untranslated regions (UTRs). BICF2P948919 is located on second SEL1L intron and the c.1972T>C mutation on exon 19. (E) Chromatograms of the c.1972T>C mutation in an affected, a carrier and a wild-type dog.
Mentions: We subsequently proceeded to map the FH ataxia locus by using a genome-wide approach. A cohort of 31 dogs, comprising 13 cases, 11 obligate carrier parents and seven non-affected siblings, were genotyped using Illumina's 22K canine SNP chip. A standard case-control association test was carried out on the 13 cases and seven full-sibling controls by using PLINK software [36]. This revealed a genome-wide significant association on CFA8 with two SNPs, BICF2P948919 and BICF2P754995, that had the best nominal and corrected p-values of praw = 1.1×10−7 and pgenome = 7.5×10−4 (Figure 4A). The association results were confirmed by utilizing a joint family-based linkage and association analysis program PSEUDOMARKER [37]. The joint analysis, which was carried out on the associated CFA8 using the entire genotyped sample cohort, identified the same locus and a single most significant SNP, BICF2P948919 (LOD score = 3.3, association p = 2.2×10−7 and joint analysis p = 4.0×10−10) (Figure 4B).

Bottom Line: Pathological and histological examinations indicated cerebellum-restricted neurodegeneration.The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort.Furthermore, our results have enabled the development of a genetic test for breeders.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus