Pedigree Analysis and Exclusion of Alpha-Tocopherol Transfer Protein (TTPA) as a Candidate Gene for Neuroaxonal Dystrophy in the American Quarter Horse

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Abstract

Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. Hypothesis: NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. Animals: 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Procedures: Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Results: Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. Conclusions and Clinical Importance: NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalJournal of Veterinary Internal Medicine
Volume27
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Neuroaxonal Dystrophies
Quarter Horse
Tissue Plasminogen Activator
Pedigree
pedigree
myeloencephalopathy
alpha-tocopherol
Horses
horses
Genes
genes
proteins
heritability
Single Nucleotide Polymorphism
alpha-tocopherol transfer protein
inheritance (genetics)
Polymerase Chain Reaction
reverse transcriptase polymerase chain reaction
mutation
vitamin E deficiency

Keywords

  • Alpha-tocopherol
  • Equine
  • Genetics
  • Vitamin E

ASJC Scopus subject areas

  • veterinary(all)

Cite this

@article{6c22cb3e150041fab645142d43a2b85f,
title = "Pedigree Analysis and Exclusion of Alpha-Tocopherol Transfer Protein (TTPA) as a Candidate Gene for Neuroaxonal Dystrophy in the American Quarter Horse",
abstract = "Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. Hypothesis: NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. Animals: 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Procedures: Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Results: Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. Conclusions and Clinical Importance: NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.",
keywords = "Alpha-tocopherol, Equine, Genetics, Vitamin E",
author = "Finno, {Carrie J} and T. Famula and Aleman, {Monica R} and Robert Higgins and Madigan, {John E} and Bannasch, {Danika L}",
year = "2013",
month = "1",
doi = "10.1111/jvim.12015",
language = "English (US)",
volume = "27",
pages = "177--185",
journal = "Journal of Veterinary Internal Medicine",
issn = "0891-6640",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Pedigree Analysis and Exclusion of Alpha-Tocopherol Transfer Protein (TTPA) as a Candidate Gene for Neuroaxonal Dystrophy in the American Quarter Horse

AU - Finno, Carrie J

AU - Famula, T.

AU - Aleman, Monica R

AU - Higgins, Robert

AU - Madigan, John E

AU - Bannasch, Danika L

PY - 2013/1

Y1 - 2013/1

N2 - Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. Hypothesis: NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. Animals: 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Procedures: Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Results: Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. Conclusions and Clinical Importance: NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.

AB - Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. Hypothesis: NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. Animals: 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Procedures: Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Results: Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. Conclusions and Clinical Importance: NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.

KW - Alpha-tocopherol

KW - Equine

KW - Genetics

KW - Vitamin E

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U2 - 10.1111/jvim.12015

DO - 10.1111/jvim.12015

M3 - Article

VL - 27

SP - 177

EP - 185

JO - Journal of Veterinary Internal Medicine

JF - Journal of Veterinary Internal Medicine

SN - 0891-6640

IS - 1

ER -