Categories: Mortality / aging (incl. embryonic lethal)

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 616267 (trait) , 613402 (trait) , 605589 (trait) , 605610 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: Loss-of function mutations in PNKP are associated with various neurological diseases in humans and are reported to cause embryonic lethality in pigs.

Species-specific name: Haplotype LA3

Species-specific description: Derks et al. (2019) identified five relatively frequent haplotypes for which there was either a deficit or a complete lack of homozygotes in large populations of Landrace (28,085) and Duroc (11,255). One of the four Landrace haplotypes (LA3) is the subject of this entry. Derks et al. (2019) identified that "a missense mutation in PNKP is a candidate to cause embryonic lethality in Landrace" [pigs]. (Edited by Emmi Payten 24/8/2021)

History: This haplotype was first identified in two commercial pig populations in Norway (Derks et al., 2019). (Edited by Emmi Payten 24/8/2021)

Mapping: Derks et al. (2019): "To identify lethal alleles segregating in the pig populations we examined genotype data from 28,085 (Landrace), and 11,255 (Duroc) animals. All animals were genotyped or imputed to a medium-density 50K SNPchip ... . The genotypes were phased to build haplotypes, and then we applied an overlapping sliding window approach to identify haplotypes that show a deficit in homozygosity ... . The analysis yielded one strong candidate haplotype (DU1) harbouring a lethal recessive allele in the Duroc population, and four candidates in the Landrace population (LA1-4), respectively." (Edited by Emmi Payten 24/8/2021)

Molecular basis: Derks et al. (2019) reported the following variant as being likely causal of the embryonic lethality due to homozygosity of haplotype LA3: "deleterious missense mutation in the PNKP gene (6:g.54880241G>T), predicted to be strongly deleterious by SIFT (0.02) and PROVEAN (-2.9). The missense mutation causes a glutamine to arginine amino acid substitution (ENSSSCP00000003467:p.Gln96Arg)"

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Derks et al. (2019) "analysed the effect of the haplotypes on fertility phenotypes including total number born (TNB), number born alive (NBA), number of stillborn (NSB), and number of mummified piglets (MUM)." The reduction in litter size (total number born) in carrier x carrier matings, compared with carrier x non-carrier matings, was 15.1%. "No significant increase in number of stillborn (NSB) or mummified piglets (MUM) was found, suggesting that homozygotes die very early in pregnancy." (Edited by Emmi Payten 24/8/2021)

Prevalence: Derks et al. (2019) reported the carrier frequency of haplotype LA2 as 4.7%, with zero observed homozygotes.

Breed: Landrace (Pig) (VBO_0001161).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: