A frameshift insertion in SGK3 leads to recessive hairlessness in Scottish Deerhounds: a candidate gene for human alopecia conditions

Abstract

Hairlessness is a breed-specific feature selected for in some dog breeds but a rare abnormality in some others such as Scottish Deerhounds (SD). In SDs, the affected puppies are born with sparse hair but lose it within the first 2 months leaving the dogs completely hairless. The previous studies have implicated variants in FOXI3 and SGK3 in hairlessness; however, the known variants do not explain hairlessness in all breeds such as SDs. We investigated the genetic cause in 66 SDs, including a litter with two hairless dogs. We utilized a combined approach of genome-wide homozygosity mapping and whole-genome sequencing of a hairless SD followed by recessive filtering according to a recessive model against 340 control genomes. Only two homozygous-coding variants were discovered in the homozygosity regions, including a 1-bp insertion in exon 2 of SGK3 . This results in a predicted frameshift and very early truncation (49/490 amino acids) of the SGK3 protein. Additional screening of the recessive variant demonstrated a full segregation with the hairlessness and a 12% carrier frequency in the SD breed. The variant was not found in the related Irish Wolfhound breed. This study identifies the second hairless variant in the SGK3 gene in dogs and further highlights its role as a candidate gene for androgen-independent hair loss or alopecia in human. Electronic supplementary material The online version of this article (10.1007/s00439-019-02005-9) contains supplementary material, which is available to authorized users.

Whole Genome Analysis of a Single Scottish Deerhound Dog Family Provides Independent Corroboration That a SGK3 Coding Variant Leads to Hairlessness

“…This SGK3 variant leads to a frameshift in the coding sequence and was predicted by Hytonen and Lohi (Hytönen and Lohi 2019) to lead to nonsense mediated decay. The lack of health issues in hairless Scottish Deerhounds, as opposed to observations in loss-of-function mouse models, suggests that perhaps SGK3 is still expressed in hairless dogs.…”

“…The resulting sequence was compared to a recent catalog of 91 million single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) identified from 144 modern breeds, together with a set of wild canids and village dogs (Plassais et al 2019). Our analysis identified the same single, high-impact variant within the coding sequence of the serum/glucocorticoid regulated kinase family member 3 (SGK3) gene as highlighted by Hytonen and Lohi (Hytönen and Lohi 2019). We have previously shown that a distinct mutation in the same gene was responsible for hairlessness in the unrelated American Hairless Terrier breed (AHT) (Parker et al 2017b).…”

“…While this study was ongoing, an analysis of eight normal and two hairless Scottish Deerhounds utilized homozygosity mapping to identify two probable variants within regions of shared allelic homozygosity on chromosome 29 (Hytönen and Lohi 2019), the most likely of which was the same insertion and subsequent frameshift in SGK3 described here. We are thus able validate these results in a fully independent data set.…”

“…A spontaneous canine model of alopecia was recently described by Hytonen and Lohi (Hytönen and Lohi 2019) in a small family of Scottish Deerhounds, a breed which typically displays a harsh and wiry coat (American Kennel Club 2017). Simultaneously, we identified an independent Scottish Deerhound family, also segregating the hairless trait.…”

Werewolf, there wolf: variants inHairlessassociated with hypotrichia and roaning in the lykoi cat breed

“…Variants in HR in other species are relatively rare, but causal variants of hairless are known in sheep [17], atrichia with papular lesions is also identified in macaques [16], and, in dolphins, evolutionary loss has led to HR as a pseudogene, leading to hypotrichosis in this mammal [20]. Various other genes cause the hairless phenotypes, such as, KRT71 in the sphynx breed [9], and FOXI3 [19] and SGK3 [59,60] in dogs.…”