Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 170500 (trait) , 603967 (gene) , 613345 (trait) , 614198 (trait) , 608390 (trait) , 168300 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1992

Species-specific name: Hyperkalemic Periodic Paralysis (HYPP)

Species-specific description: HYPP in horses is an autosomal incompletely dominant disorder characterized by episodic attacks of muscle tremors, weakness and paralysis with associated increased serum potassium concentration (Rudolph et al., 1992; Animal Genetics). While HYPP is considered a defect by the American Quarter Horse Association (AQHA), some breeders consider the muscular phenotype attractive and select for this phenotype. Thus, the AQHA refuses to register homozygous animals, but still registers heterozygotes. {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

History: First described only in the mid-1980s (Cox, 1985; Steiss and Naylor, 1986). This is the first equine disorder for which a causative mutation was identified (Rudolph et al., 1992 Nature Genetics). In 1996 Bowling et al. (1996 Animal Genetics) reported that all horses possessing the variant were descendants of a “Stallion 1” subsequently identified as IMPRESSIVE, born in 1969. {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Inheritance: Naylor et al. (1999) compared the clinical responses of heterozygotes to homozygotes for the variant causing HYPP and determined that homozygotes are more severely affected, demonstrating the partial dominant mode of inheritance. {text supplied by Professor E. Bailey and students; 20 March 2019}

Mapping: Noting that this disorder in horses is very similar to a disorder in humans which is due to mutations in the adult skeletal muscle sodium channel gene (SNC4A), Rudolph et al. (1992, Animal Genetics) isolated the orthologous horse SNC4A gene. Using a polymorphism identified in this horse gene and the observed polymorphism at the horse HYPP locus, these authors then showed complete linkage (theta = 0) between the SNC4A gene and the HYPP disorder locus in horses. {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019} This disorder therefore provides an excellent example of how knowledge of comparative genetics can be put to good use in elucidating the molecular basis of disorders.

Molecular basis: The molecular basis of this disorder was first reported by Rudolph et al. (1992, Nature Genetics). Having established that the horse gene for adult skeletal muscle sodium channel (SNC4A) is completely linked with this disorder (see Mapping section above), Rudolph et al. (1992, Nature Genetics) identified the causative mutation as a missense mutation causing an amino acid substitution from phenylalanine to leucine in the gene encoding the alpha chain of the adult skeletal muscle sodium channel, resulting in increased sodium permeability across the skeletal muscle cell membrane. The SIFT score for this variant is 0.01 (deleterious) (Ensembl's Variant Effect Predictor). {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Clinical features: Muscle fasciculation and spasm; weakness; recumbency; episodic attacks of muscle tremors, weakness and paralysis with associated increased serum potassium concentration; pronounced muscularity; attacks follow diet changes, fasting, stressful circumstances or after consumption of alfalfa hay which is high in potassium (Steiss & Naylor 1986; Spier et al., 1990) {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Prevalence: Quarter Horse; Bowling et al. (1996) reported that all horses possessing the variant were descendants of a “Stallion 1” subsequently identified as IMPRESSIVE, born in 1969. Tryon et al.( 2009) tested subpopulations of Quarter Horses and found the variant absent among cutting horses, cow horses, reining horses and racing horses. It was present among barrel racing horses (allele frequency 0.006), western pleasure horses (allele frequency 0.013) and halter horses (allele frequency 0.299). The variant was also found among paint horses that were crosses from Quarter Horse. {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Breed: Quarter Horse (Horse) (VBO_0001057).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: