Bald thigh syndrome in sighthounds-Revisiting the cause of a well-known disease.

Magdalena A T Brunner,Natasha Buchs,Manfred Heller,Susanne Erpel,Anina Bauer,Sophie Braga-Lagache,Silvia Rüfenacht,Vidhya Jagannathan,Monika M Welle,Tosso Leeb,Dominique J Wiener,Michel Simon

doi:10.1371/journal.pone.0212645

Magdalena A T Brunner, Natasha Buchs + Show 10 more

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https://doi.org/10.1371/journal.pone.0212645

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Abstract

Bald thigh syndrome is a common hair loss disorder in sighthounds. Numerous possible causes, including environmental conditions, trauma, stress, endocrinopathies and genetic components have been proposed, but only endocrinopathies have been ruled out scientifically. The overall goal of our study was to identify the cause of bald thigh syndrome and the pathological changes associated with it. We approached this aim by comparing skin biopsies and hair shafts of affected and control dogs microscopically as well as by applying high-throughput technologies such as genomics, transcriptomics and proteomics. While the histology is rather unspecific in most cases, trichogram analysis and scanning electron microscopy revealed severe structural abnormalities in hair shafts of affected dogs. This finding is supported by the results of the transcriptomic and proteomic profiling where genes and proteins important for differentiation of the inner root sheath and the assembly of a proper hair shaft were downregulated. Transcriptome profiling revealed a downregulation of genes encoding 23 hair shaft keratins and 51 keratin associated proteins, as well as desmosomal cadherins and several actors of the BMP signaling pathway which is important for hair shaft differentiation. The lower expression of keratin 71 and desmocollin 2 on the mRNA level in skin biopsies corresponded with a decreased protein expression in the hair shafts of affected dogs. The genetic analysis revealed a missense variant in the IGFBP5 gene homozygous in all available Greyhounds and other sighthounds. Further research is required to clarify whether the IGFBP5 variant represents a predisposing genetic risk factor. We conclude from our results that structural defects in the hair shafts are the cause for this well-known disease and these defects are associated with a downregulation of genes and proteins essential for hair shaft formation. Our data add important knowledge to further understand the molecular mechanisms of HF morphogenesis and alopecia in dogs.

Highlights

One of the most characteristic features of hair follicles (HFs) is their self-renewal throughout the entire life of an individual to continuously produce new hair shafts (HSs)
We addressed this by 1) histological evaluation of skin biopsies from Greyhounds with Bald thigh syndrome (BTS) in comparison to skin biopsies from haired Greyhounds, 2) investigation of the HS structure using trichograms and scanning electron microscopy of affected and control Greyhounds and Whippets, 3) transcriptome analysis of skin biopsies from affected and control Greyhounds to identify differences in gene expression in order to gain insight into the molecular mechanisms which may be involved in the pathogenesis of BTS, 4) assessment of the protein composition of HSs of affected and control dogs, and 5) comparison of whole genome sequence data from affected and unaffected Greyhounds in comparison to genome sequence data of dogs from other breeds that are not predisposed to BTS
Histological findings were similar in all biopsies investigated and no clear difference between biopsies taken from alopecic skin and haired skin could be observed

Summary

Introduction

One of the most characteristic features of hair follicles (HFs) is their self-renewal throughout the entire life of an individual to continuously produce new hair shafts (HSs). The self-renewal process is organized in the hair cycle during which the HF undergoes periodic stages of growth (anagen), regression (catagen), and quiescence (telogen) [1, 2]. The HS elongates during late anagen by the division of lineage-restricted matrix progenitors. These cells divide and migrate upward while differentiating to trichocytes. The precipitation of keratins and the loss of water results in terminal cornification, associated with hardening of the HS. During this process cell membranes of neighbouring trichocytes become more closely apposed and the number of cell junction complexes becomes higher, indicating an increased cellular adhesion and intercellular communication. At the level of the proximal end of the isthmus the mature HS detaches from the IRS (Adamson‘s fringe) [3]

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