In other species: dog

Categories: Immune system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600899 (gene) , 615966 (trait)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1997

Species-specific name: Severe Combined Immunodeficiency Disease (SCID)

History: This disorder was first described by McGuire and Poppie (1973), in two Arabian foals that were full siblings , each of which exhibited deficiency of B- and T-lymphocyte function. Further investigation of families indicated this was a recessive genetic disorder found among Arabian horses. Comparative functional candidate genes from human SCID (ADA, NP) were considered and rejected (McGuire et al. 1976 ) before the gene (PRKDC) and variant responsible for the trait was found. {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019}

Mapping: Using 23 microsatellite markers on a carrier stallion and 19 affected offspring, Bailey et al. (1997) showed linkage of this disorder to the markers HTG8 and HTG4. Knowing that the DNAPK gene had recently been implicated in mouse SCID (Blunt et al., 1996; PNAS 93: 10285-90), these authors then used a somatic cell hybrid panel to show that the equine DNA-PK gene is syntenic with those same two microsatellite markers, thereby implicating DNAPK as a very strong candidate gene for equine SCID. By FISH analysis, they also showed that this gene physically maps to horse chromosome ECA9p12.

Molecular basis: The molecular basis of SCID in horses was discovered by Shin et al. (1997), who used the comparative candidate-gene approach (based on work with SCID mice; see Mapping section). By sequencing the equine homologue of DNAPK, Shin et al. (1997) showed that SCID in horses is due to a 5bp deletion giving rise to a frameshift in that gene, resulting in the lack of full-length kinase, and absence of kinase activity. The DNAPK gene was previously called DNA-PKcs; it is now called PRKDC (protein kinase, DNA-activated, catalytic polypeptide). The Ensembl Variant Effect Predictor (VEP) predicts the effect of this variant to be “high”. {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019}

Clinical features: Affected foals are clinically normal at birth but beginning at about 10 days of age they develop a range of clinical signs, particularly bronchopneumonia and diarrhea with which adenoviruses are peculiarly associated (Studdert, 1978). {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019} The "combined" nature of this disorder was highlighted by McGuire and Poppie (1973): “The defect in the B-lymphocyte system was shown by hypogammaglobulinemia, lymphopenia and absence of germinal centers. The almost total absence of thymic tissue in one foal and the lack of thymic dependent lymphocytes in the spleens of both foals demonstrate a T-cell defect.” {with thanks to Professor E. Bailey; 20 March 2019}

Prevalence: AbouEl Ela et al. (2018) reported a zero frequency of the c.9478_9482del variant in a sample of 103 Egyptian horses, including 33 randomly-selected Arab horses.

Breed: Arab (Horse) (VBO_0000905).
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: