Whole genome sequencing identifies missense mutation in MTBP in Shar-Pei affected with Autoinflammatory Disease (SPAID)

Julia Metzger,Ann-Kathrin Uhde,Ottmar Distl,Marion Hewicker-Trautwein,Anna Nolte

doi:10.1186/s12864-017-3737-z

Julia Metzger, Ann-Kathrin Uhde + Show 3 more

Open Access

https://doi.org/10.1186/s12864-017-3737-z

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Abstract

BackgroundAutoinflammatory diseases in dogs are characterized by complex disease processes with varying clinical signs. In Shar-Pei, signs of inflammation including fever and arthritis are known to be related with a breed-specific predisposition for Shar-Pei Autoinflammatory Disease (SPAID).ResultsClinical and histopathological examinations of two severely SPAID-affected Shar-Pei revealed signs of inflammation including fever, arthritis, and perivascular and diffuse dermatitis in both dogs. A multifocal accumulation of amyloid in different organs was found in one SPAID-affected case. Whole genome sequencing resulted in 37 variants, which were homozygous mutant private mutations in SPAID-affected Shar-Pei. Nine SNVs with predicted damaging effects and three INDELs were further investigated in 102 Shar-Pei affected with SPAID, 62 unaffected Shar-Pei and 162 controls from 11 different dog breeds. The results showed the missense variant MTBP:g.19383758G > A in MTBP to be highly associated with SPAID in Shar-Pei. In the region of this gene a large ROH (runs of homozygosity) region could be detected exclusively in the two investigated SPAID-affected Shar-Pei compared to control dog breeds. No further SPAID-associated variant with predicted high or moderate effects could be found in genes identified in ROH regions. This MTBP variant was predicted to affect the MDN2-binding protein domain and consequently promote proinflammatory reactions. In the investigated group of Shar-Pei older than six years all dogs with the mutant genotype A/A were SPAID-affected whereas SPAID-unaffected dogs harbored the homozygous wildtype (G/G). Shar-Pei with a heterozygous genotype (G/A) were shown to have a 2.13-fold higher risk for disease development, which gave evidence for an incomplete dominant mode of inheritance.ConclusionsThe results of this study give strong evidence for a variant in MTBP related with proinflammatory processes via MTBP-MDM2 pathway. Thus, these results enable a reliable detection of SPAID in Shar-Pei dogs.

Highlights

Autoinflammatory diseases in dogs are characterized by complex disease processes with varying clinical signs
We investigated genetic variants derived from generation sequencing (NGS) data to identify potential causative mutations which might be involved in the development of autoinflammatory processes and play a significant role in triggering Shar-Pei Autoinflammatory Disease (SPAID) in Shar-Pei
Phenotype Clinical investigations and patient histories recorded by a questionnaire resulted in 102 Shar-Pei with clinical signs consistent with SPAID and 62 unaffected dogs

Summary

Introduction

Autoinflammatory diseases in dogs are characterized by complex disease processes with varying clinical signs. Further droplet digital PCR (ddPCR) analysis of the 16.1 Kb copy number variation (CNV) upstream of HAS2 revealed stable CNV alleles in this region in contrast to continuous alleles previously detected by real-time PCR and subsequently suggested an association with SPAID [15]. This breed specific CNV was suggested to be inherited in a bi-allelic way and proposed to explain 9.7% of the genetic variance whereas the influence of further potential causative variants and triggers for SPAID were still unclear [15]. Various genes have been shown to be involved in human autoinflammatory processes and were found to interact with each other in triggering recurrent episodes of inflammation [18,19,20,21,22,23]

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