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

Marjo K Hytönen,Hannes Lohi

doi:10.1007/s00439-019-02005-9

Marjo K Hytönen, Hannes Lohi

Open Access

https://doi.org/10.1007/s00439-019-02005-9

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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.

Highlights

Purebred dog breeds exhibit numerous different coat types and some breeds lack the coat altogether
Only two variants were located within the regions of shared allelic homozygosity and were both on chromosome 29: a nonsynonymous change in zinc-finger homeobox 4 (ZFHX4) gene and a frameshift insertion in serum/glucocorticoid regulated kinase family member 3 (SGK3)
ZFHX4 has an unknown function, but it has been suggested as a candidate gene for ptosis (McMullan et al 2002) and to be involved in neural and muscle differentiation based on the expression pattern (Hemmi et al 2006)

Summary

Introduction

Purebred dog breeds exhibit numerous different coat types and some breeds lack the coat altogether. The Chinese Crested and Peruvian and Mexican Hairless dogs are bred for almost hairless appearance They have sparse or no body hair, but varying amounts of hair on the head, the tip of the tail, and distal parts of legs are allowed. The trait is dominant and embryonic lethal as homozygous It is caused by a 7-bp duplication, which results in a frameshift and a premature stop codon in the forkhead box I3 (FOXI3) gene (Drögemüller et al 2008). A member of the same gene family, FOXI2, has been recently suggested to contribute to ectodermal dysplasia (Kurban et al 2017)

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