Studies in Abhd5-/- knockout mice showed drastically reduced triglyceride (TG) hydrolase activity in the epidermis. ABHD5 also activates adipose triglyceride lipase (ATGL), which catalyzes the initial step of lipolysis converting TG to diglycerides (DG) (Zimmermann et al. The arrow indicates the dog that was used for whole-genome sequencing. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, et al. The clinical and histological presentation of ICH2-affected dogs strongly resembled that of the well-known PNPLA1-related ichthyosis in Golden Retrievers (Grall et al. The identified candidate variant was a 14bp deletion in the last exon of ABHD5, XM_542689.5:c.1006_1019del (Figure4, B and C). Genotype data for 44 Golden Retrievers comprising dogs from 7 litters and their parents were obtained with 220 k Illumina CanineHD BeadChips by Geneseek/Neogen (Supplementary File S1, 11 unaffected parents, 14 affected, and 19 unaffected offspring). Nonsyndromic ichthyoses refer to those with the phenotypic manifestation of the disease limited to the skin whereas syndromic ichthyoses additionally involve other organs. 7g7*"=70}F{,>@D: JsHlW,;TFl0P,\1(!4P#x;DTQV|)1B_nA[}#7 Evaluating Illumina-, Nanopore-, and PacBio-based genome assembly strategies with the bald notothen, Modular safe-harbor transgene insertion for targeted single-copy and extrachromosomal array integration in, Quantitative Evaluation of Nonlinear Methods for Population Structure Visualization & Inference, A chromosome-level reference genome of a Convolvulaceae species, Characterization of the cluster MabR prophages of, https://doi.org/10.1093/g3journal/jkab397, https://creativecommons.org/licenses/by/4.0/, Receive exclusive offers and updates from Oxford Academic, All variants in the affected Golden Retriever, Private protein-changing variants in critical interval, Copyright 2022 Genetics Society of America. Guagure E, Bensignor E, Muller A, Degorce-Rubiales F, Andre C. Guagure E, Bensignor E, Kry S, Degorce-Rubiales F, Muller A, et al. Assuming that the disease allele is rare in the dog population, we filtered for private homozygous variants that were absent from 795 control genomes (Supplementary Table S2). (A) Adherent scales on the inner pinna. Note the multiple inbreeding loops within this pedigree. CDS is a rare autosomal recessive inherited syndromic form of ichthyosis. Histopathology of a Golden Retriever with ICH2. This protein is involved in the biosynthesis of major components of the skin barrier formation, especially -O-acylceramide (Ghosh et al. Ichthyoses comprise a heterogeneous group of cornification disorders characterized by generalized dry and scaly skin. Markers with call rates <100% and markers on the sex chromosomes were excluded. _NO~r:=j! Contrasting the genome sequence of an affected dog against 795 control genomes identified a single private homozygous coding variant within the critical interval, a 14bp deletion in the last exon of the ABHD5 gene. 2012), together with NCBI annotation release 105 for the CanFam 3.1 genome reference assembly was used. 2008; Ohno et al. Casal ML, Wang P, Mauldin EA, Lin G, Henthorn PS. The genome sequence data were submitted to the European Nucleotide Archive (ENA). 2015; OMIA 001973-9615). The output intervals were matched against the intervals from linkage analysis in Excel spreadsheets to find overlapping regions (Supplementary Table S1). The Golden Retrievers in this study were privately owned and skin biopsies and blood samples for diagnostic purposes were collected with the consent of their owners. R;[EY 2019). Epidermolytic ichthyoses are accompanied by epidermolytic hyperkeratosis at the ultrastructural level. We confirmed the presence of this variant in the index case by Sanger sequencing and genotyped all 85 relatives. Ichthyoses can be further subdivided into epidermolytic and nonepidermolytic ichthyoses. Histopathological examinations showed lamellar, orthokeratotic hyperkeratosis, and mildly hyperplastic epidermis that led to the diagnosis of a nonepidermolytic ichthyosis. We used Sanger sequencing to confirm the candidate variant ABHD5:c.1006_1019del. All positions correspond to the CanFam3.1 reference genome assembly. Sarah Kiener, Dominique J Wiener, Kaitlin Hopke, Alison B Diesel, Vidhya Jagannathan, Elizabeth A Mauldin, Margret L Casal, Tosso Leeb, ABHD5 frameshift deletion in Golden Retrievers with ichthyosis, G3 Genes|Genomes|Genetics, Volume 12, Issue 2, February 2022, jkab397, https://doi.org/10.1093/g3journal/jkab397. Haydar Eskiocak A, Missaglia S, Moro L, Durdu M, Tavian D. Jagannathan V, Drgemller C, Leeb T, Aguirre G, Andr C, et al. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. The defective epidermal TG catabolism led to an impaired synthesis of acylceramides and defective formation of the corneocyte lipid envelope resulting in a dysfunctional permeability barrier of the skin (Radner et al. 2019). The other dogs are shown in gray. Corresponding author: Institute of Genetics, University of Bern, Bremgartenstrasse 109a, 3001 Bern, Switzerland. [b)%+81H (*.XQUHN2Hm [N0`QPJ&"A9[0h-HQe_ofI\y@&JiVsOz|-+P$Ir%GY*l'Q~Vk|G6DuW6U,HV_!-+!!l>uWx@-iUui^OI}X,C=>q_hEo,u.d7y[c!NU&+^V|y F?Db !8o x af;.6IsOJCX8tU%?3!Z%kN5 s/@@Qw( 2007), markers on the sex chromosomes or with unknown positions were removed. Chanarin I, Patel A, Slavin G, Wills EJ, Andrews TM, et al. The skin biopsies of affected dogs showed moderate epidermal hyperplasia without dermal inflammation. We further removed markers that had missing genotypes in any of the 44 dogs, Mendel errors, or a minor allele frequency <0.01. The 11 parents of the 14 cases who represent obligate carriers were all heterozygous. The ABHD5:c.1006_1019del frameshift deletion identified in the affected Golden Retrievers of this study alters the last 14 codons of the open reading frame. The pedigree showed multiple inbreeding loops and was strongly suggestive for a monogenic autosomal recessive inheritance (Figure3). The authors thank Nathalie Besuchet Schmutz, Catia Coito, Marion Ernst, and Daniela Steiner for expert technical assistance, the Next Generation Sequencing Platform of the University of Bern for performing the high-throughput sequencing experiments, and the Interfaculty Bioinformatics Unit of the University of Bern for providing high performance computing infrastructure. A splice site variant in SLC27A4 was described in Great Danes with a clinically severe, autosomal recessive syndromic ichthyosis (Metzger et al. The dogs were organized in four subfamilies (see Materials and Methods and Figure3). Whole-genome sequencing of an affected dog revealed a single protein-changing variant within this region that was not present in 795 control genomes. indicates an estimated proportion of the four subfamilies that show linkage. A tped-file containing the markers on chromosome 23 was visually inspected in an Excel spreadsheet to precisely delimit the homozygous shared haplotype in the cases (Supplementary Table S1). Histologically, the epidermis in ICH2-affected dogs is thicker than in dogs with the PNPLA1-related ichthyosis dogs and this may correspond with a more severe barrier defect. 1974; Chanarin et al. 2013). The LOD score of the linked interval on chromosome 23 was 2.75 (Table1, Supplementary Figure S1). ICH2 cases tend to have more keratinocytes with perinuclear clear spaces than dogs with the PNPLA1-related ichthyosis. Radner FP, Streith IE, Schoiswohl G, Schweiger M, Kumari M, et al. The remaining 61 unaffected relatives were either heterozygous or homozygous for the wildtype allele. Ichthyoses are hereditary skin disorders characterized by the formation of scales and defects in the outermost layer of the epidermis. In American Bulldogs, a frameshift deletion in NIPAL4 was found to cause autosomal recessive congenital ichthyosis (Casal et al. This research was funded by the Swiss National Science Foundation, grant number 310030_200354. Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland. We propose to term this specific phenotype Golden Retriever ichthyosis type 2 (ICH2, OMIA 002368-9615). This strongly suggests an essential function of the C-terminal tail of ABHD5 and supports the hypothesis that the observed ABHD5:c.1006_1019del frameshift deletion is indeed causative for the ichthyosis in the investigated Golden Retrievers. A physical examination was performed by the attending veterinarians. In this study, we investigated 14 Golden Retrievers with a new form of ichthyosis termed ICH2 that so far appears to be limited to dogs from North America. is affiliated with the PennGen Laboratory, which offers genetic testing for dogs. The underlying genetic defect is a homozygous insertion-deletion (indel) variant in PNPLA1 encoding patatin like phosphatase domain containing 1. Thick white scale was adherent to the concave surface of the pinnae (Figure1). 2010). Experienced breeders reported more severe and adherent scaling in ICH2-affected Golden Retrievers. ABHD5 loss-of-function variants in humans were reported to cause Chanarin-Dorfman syndrome (CDS) (OMIM # 275630, Dorfman et al. Lefevre C, Jobard F, Caux F, Bouadjar B, Karaduman A, et al. The classification of ichthyoses distinguishes between syndromic and nonsyndromic forms. The authors are grateful to all dog owners who donated samples and shared health and pedigree information of their dogs. A 300bp PCR product (or 305bp in case of the mutant allele) was amplified with the primers 5-GGC CCT GAT AGT GAA GGA CA-3 (Primer F) and 5-TCC TAA CAC CTG CTC CTG CT-3 (Primer R). ABHD5 encodes - hydrolase domain containing 5 also known under the alias name CGI-58. M.L.C. 2017; OMIA 002099-9615). Numerous keratinocytes have perinuclear clear spaces (arrows). ; Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, et al. 2010) in gVCF mode as described (Jagannathan et al. All authors have read and agreed to the published version of the manuscript. Two to four 46mm skin punch biopsies per dog were taken and routinely processed for histopathology. Pedigree of the investigated Golden Retriever family. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, et al. ; investigation, S.K., D.J.W., K.H., A.B.D., E.A.M., and M.L.C. In this study, we investigated 14 Golden Retrievers with scales that were not homozygous for the mutant PNPLA1 allele suggesting a genetically distinct new form of ichthyosis. Numbering within the canine ABHD5 gene corresponds to the NCBI RefSeq accession numbers XM_542689.5 (mRNA) and XP_542689.2 (protein). It causes a frameshift, resulting in a premature stop codon and altering the last 14 codons of the open reading frame, XP_542689.2:p.(Asp336Serfs*6). 2008). The first case report is from 2004 (Hall and Yager 2004) and the disease phenotype has been well characterized in the following years (Guagure et al. The formal genomic designation of the variant is Chr23:2,587,0002,587,013del (CanFam3.1). 2001; Grall et al. 2009). Sanger sequences were analyzed with the Sequencher 5.1 software (Gene Codes Corporation, Ann Arbor, MI, USA). An autosomal recessive nonepidermolytic ichthyosis in Jack Russell Terriers is caused by a LINE-1 insertion into the TGM1 gene (Credille et al. The clinical signs together with the histopathological findings led to the diagnosis of a nonepidermolytic ichthyosis. 2018). ICH2 affected dogs had large white to gray and powdery to adherent scale throughout the hair coat. Typical findings are intracellular vacuolization and formation of small intraepidermal blisters (Oji et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (. 2009). The other authors declare no conflict of interest. Dorfman ML, Hershko C, Eisenberg S, Sagher F. Ghosh AK, Ramakrishnan G, Chandramohan C, Rajasekharan R. Grall A, Guagure E, Planchais S, Grond S, Bourrat E, et al. A lack of either ABHD5 or PNPLA1 leads to ichthyosis in humans (Lefevre et al. 2005; OMIA 001415-9615). 2001). In the last step of this pathway, ABHD5 acts as a coactivator of PNPLA1 and may help to provide the required triacylglycerides within the endoplasmic reticulum (Ohno et al. After treatment with exonuclease I and alkaline phosphatase, we sequenced the amplicons in both directions on an ABI 3730 DNA Analyzer (Thermo Fisher Scientific Corporation, Waltham, MA, USA). Clinical images from an 11-week-old Golden Retriever with ICH2. Results of variant filtering in the ICH2 affected Golden Retriever against 795 control genomes. The reads were mapped to the dog CanFam3.1 reference genome assembly as previously described (Jagannathan et al. The genotypes at this variant showed perfect cosegregation with the ichthyosis phenotype in a large family comprising 14 cases and 72 controls. In this study, we investigated 14 Golden Retrievers with clinical and histopathological signs of nonepidermolytic ichthyosis. All 14 available cases were homozygous for the deletion. For all dogs, the call rate was >95%. Variant calling was performed using GATK HaplotypeCaller (McKenna et al. Published by Oxford University Press on behalf of Genetics Society of America. ; writingoriginal draft, S.K., D.J.W., K.H., A.B.D., E.A.M., M.L.C., and T.L. Mapping of the ICH2 locus and details of the ABHD5:c.1006_1019del variant. They comprised 86 closely related dogs including 14 ICH2 affected and 72 unaffected relatives originating from North America. The sequence data were deposited under study accession PRJEB16012 and sample accession SAMEA8797074 at the European Nucleotide Archive. Oxford University Press is a department of the University of Oxford. For homozygosity mapping, the genotype data for the 14 ICH2 affected dogs were used. This differentiation is light microscopy based. (C) Sanger sequencing confirmed the detected 14bp frameshift deletion. Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Uitto J, Youssefian L, Saeidian AH, Vahidnezhad H. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, et al. In dogs, several breed-specific ichthyoses have been described. 2008). 2008; Mauldin et al. To predict the functional effects of the called variants, the SnpEff software (Cingolani et al. (B) Integrative Genomics Viewer (IGV) screenshot showing the position of the deletion in the short-read alignments of the ICH2 affected dog. 2004; Lass et al. Hematoxylin and eosin (H&E) stained slides were reviewed by board certified veterinary pathologists (DJW and EAM). The exact coordinates of the critical interval were Chr23:112,734,912 (Supplementary Table S1). ; writingreview and editing, S.K., D.J.M., K.H., A.B.D., V.J., E.A.M., M.L.C., and T.L. A heterozygous missense variant in ASPRV1 caused an autosomal dominant form of nonepidermolytic ichthyosis in a German Shepherd (Bauer et al. Our data in dogs together with the knowledge on the effects of ABHD5 variants in humans strongly suggest ABHD5:c.1006_1019del as candidate causative genetic variant for a new canine form of ichthyosis, which we propose to designate as Golden Retriever ichthyosis type 2 (ICH2). In humans, variants in ABHD5 cause Chanarin-Dorfman syndrome, a neutral lipid storage disease with ichthyosis. 2002) were applied. They also acknowledge all researchers who deposited dog or wolf whole-genome sequencing data into public databases. (A) Skin biopsy from an affected dog reveals marked thickening of the epidermis with expansion of the stratum corneum by laminar orthokeratotic hyperkeratosis. More than ten pathogenic human ABHD5 variants have been described, many of which are affecting the - hydrolase domain, lipid binding region, pseudocatalytic domain, or acyltransferase domain (Lefevre et al. They include the last 10 codons of the - hydrolase domain (Schweiger et al. Genotypes at the ABHD5: c.1006_1019del variant in Golden Retrievers of North American and European origin. The identified variant is a 14bp deletion in the ABHD5 gene (c.1006_1019del), leading to a frameshift and altering the last 14 codons p.(Asp336Serfs*6). Squares represent males and circles represent females. Despite the phenotypic similarity to the PNPLA1-related ichthyosis, none of these dogs carried the mutant PNPLA1 allele in a homozygous state. 2010). Subsequently, targeted genotyping of dogs was performed by fragment length analysis of PCR products on a 5200 Fragment Analyzer (Agilent, Basel, Switzerland). By combining linkage analysis and homozygosity mapping, we determined the critical interval for the disease-causing genetic variant. The 14 available cases belonged to seven different litters, each with unaffected parents. Numerous keratinocytes in the granular layer contained perinuclear clear spaces (Figure2). Both male and female dogs were affected. In the present study, we therefore aimed to characterize this presumably new form of inherited ichthyosis and to unravel the causative genetic variant. The mutant allele was absent from 396 Golden Retrievers of European origin (Table3, Supplementary Table S4). However, in only six of the canine ichthyoses, the underlying genetic defect has been identified (Mauldin 2013; Leeb et al. 2001; Schweiger et al. Using PLINK v1.9 (Purcell et al. The Author(s) 2021. (A) Combined linkage and homozygosity mapping revealed a single overlapping region on chromosome 23 indicated by an arrow. In dogs, at least six different breed-specific ichthyoses including a relatively common PNPLA1-related autosomal recessive ichthyosis in Golden Retrievers are known. 2012) was genotyped by Sanger sequencing of PCR amplicons as described above. (B) Thick scales on the ventral thorax and (C) abdominal hyperpigmentation. Credille KM, Barnhart KF, Minor JS, Dunstan RW. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. An Illumina TruSeq PCR-free library with an insert size of 330bp was prepared from one ICH2 affected dog and sequenced at 26x coverage on an Illumina NovaSeq 6000 instrument. Further studies are warranted to clarify whether the phenotypic changes in the affected dogs are limited to the skin or whether ICH2 also affects other organs like CDS in humans. A comparable ABHD5 nonsense variant truncating the last 14 codons of the homologous human sequence was reported in four CDS patients from a consanguineous family (Aggarwal et al. The abdominal skin was mildly hyperpigmented. 1975; Lefevre et al. Email: Merlinrapid analysis of dense genetic maps using sparse gene flow trees, Novel nonsense mutation of ABHD5 in Dorfman-Chanarin syndrome with unusual findings: a challenge for genotype-phenotype correlation, Clinical and genetic characterization of ChanarinDorfman syndrome, Cornification defect in the golden retriever: clinical, histopathological, ultrastructural and genetic characterisation, A defect in NIPAL4 is associated with autosomal recessive congenital ichthyosis in American Bulldogs, Neutral-lipid storage disease: a new disorder of lipid metabolism, A program for annotating and predicting the effects of single nucleotide polymorphisms, Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs, Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs, Ichthyosiform dermatosis with systemic lipidosis, CGI-58, the causative gene for Chanarin-Dorfman syndrome, mediates acylation of lysophosphatidic acid, PNPLA1 mutations cause autosomal recessive congenital ichthyosis in Golden Retriever dogs and humans, Epidemiological, clinical, histopathological and ultrastructural aspects of ichthyosis in Golden Retrievers: a report of 50 cases, Clinical, histopathological and genetic data of ichthyosis in the Golden Retriever: a prospective study, Dog Biomedical Variant Database Consortium (DBVDC), A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves, Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome, Genetic testing in veterinary dermatology, Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome, Canine ichthyosis and related disorders of cornification, The clinical and morphologic features of nonepidermolytic ichthyosis in the Golden Retriever, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data, Molecular mechanism of the ichthyosis pathology of ChanarinDorfman syndrome: stimulation of PNPLA1-catalyzed -O-acylceramide production by ABHD5, Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009, PLINK: a tool set for whole-genome association and population-based linkage analyses, Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58), Inherited ichthyoses/generalized Mendelian disorders of cornification, Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5, Molecular genetics of keratinization disorders - what's new about ichthyosis, Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. The identified candidate causative variant enables genetic testing to prevent the unintentional breeding of affected puppies. ; data curation, V.J. Aggarwal S, Maras JS, Alam S, Khanna R, Gupta SK, et al. 2019). A 389bp (or 375bp in case of the mutant allele) PCR product was amplified from genomic DNA using AmpliTaqGold360Mastermix (Thermo Fisher Scientific, Waltham, MA, USA) and primers 5-CTG CTG GCC CTG TCA TTA GT-3 (Primer F) and 5-CAG GCT CTC TCT CCC ACA TT-3 (Primer R). It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Inner pinna rates < 100 % and markers on the ventral thorax and ( ). Studies in Abhd5-/- knockout mice showed drastically reduced triglyceride ( TG ) hydrolase activity in the granular layer contained clear... S, Khanna R, Haemmerle G, et al name CGI-58 from 396 Golden of! 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