Whole-Genome Sequencing of a Canine Family Trio Reveals a <i>FAM83G</i> Variant Associated with Hereditary Footpad Hyperkeratosis

Sayyab, Shumaila; Viļuma, Agnese; Bergvall, Kerstin; Brunberg, Emma; Jagannathan, Vidhya; Leeb, Tosso; Andersson, Gerhard; Bergström, Tomas F.

doi:10.1534/g3.115.025643

Cited by 20 publications

(28 citation statements)

References 49 publications

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“…The identification of the causative variant will enable easier diagnosis of similar cases in the future and selective breeding to avoid the spread of this disease in the breed. Application of WGS to identify the causative mutation of MPS in Boston Terriers not only enriches our knowledge about the molecular mechanisms of this debilitating diseases but also augments recent studies to prove the efficiency of this technique in canine rare disease gene discovery 45,46 . www.nature.com/scientificreports www.nature.com/scientificreports/ Radiological assessment.…”

Section: Discussionmentioning

confidence: 93%

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Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Mansour

Woolard

Vernau

et al. 2020

Sci Rep

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Mucopolysaccharidosis (MPS) is a metabolic storage disorder caused by the deficiency of any lysosomal enzyme required for the breakdown of glycosaminoglycans. A 15-month-old Boston Terrier presented with clinical signs consistent with lysosomal storage disease including corneal opacities, multifocal central nervous system disease and progressively worsening clinical course. Diagnosis was confirmed at necropsy based on histopathologic evaluation of multiple organs demonstrating accumulation of mucopolysaccharides. Whole genome sequencing was used to uncover a frame-shift insertion affecting the alpha-L-iduronidase (IDUA) gene (c.19_20insCGGCCCCC), a mutation confirmed in another Boston Terrier presented 2 years later with a similar clinical picture. Both dogs were homozygous for the IDUA mutation and shared coat colors not recognized as normal for the breed by the American Kennel Club. In contrast, the mutation was not detected in 120 unrelated Boston Terriers as well as 202 dogs from other breeds. Recent inbreeding to select for recessive and unusual coat colors may have concentrated this relatively rare allele in the breed. The identification of the variant enables ante-mortem diagnosis of similar cases and selective breeding to avoid the spread of this disease in the breed. Boston Terriers carrying this variant represent a promising model for MpS i with neurological abnormalities in humans.Mucopolysaccharidosis (MPS) is a type of lysosomal storage disease caused by a deficiency of enzymes integral to the breakdown of glycosaminoglycans (GAGs). This serious condition, described in many species including humans and dogs, leads to the accumulation of metabolites of the GAG degradation pathway within lysosomes along with increased urinary excretion of these metabolites 1 . There are 11 known enzymes that regulate the catabolism of four different GAGs. The GAGs affected in each variant of MPS are dependent upon which enzyme is deficient 2 .In people, MPS is a chronic disease with a progressive course. Neurological abnormalities are a major component of the disease. The progressive cerebral disease typically occurs in MPS III and severe forms of MPS I, II, and VII but chronic hearing loss and vision impairment can occur in all types. Thickening of meninges and diffuse changes to the brain's white matter are also common 3,4 . Most MPS types, except for MPS III, are associated with skeletal abnormalities, joint disease, short stature and abnormal facies 5 . Cardiovascular dysfunctions like valvular heart disease, narrowing of coronary arteries, and eccentric hypertrophy are universal to all subtypes

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Section: Discussionmentioning

confidence: 93%

“…In dogs, WGS has been successfully used in disease gene discovery in a family trio. In the absence of candidate disease genes, additional genotyping of extra cases was needed 45 . WGS was also able to identify the causative coding variant of oculocutaneous albinism in candidate genes 46 .…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Mansour

Woolard

Vernau

et al. 2020

Sci Rep

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“…Phenotype-driven transgenic mice displaying spontaneous wooly hair phenotype were mapped to homozygous mutations on the FAM83G gene [ 38 ]. Two autosomal recessive point mutations on the FAM83G gene in dogs (R52P) and humans (A34E) have been reported to cause hereditary palmoplantar (footpad) hyperkeratosis syndrome, which is characterlocalised by thickening of footpads, epidermal hyperplasia and abnormal hair morphology [ 39 – 41 ]. Given the fundamental roles of Wnt signalling in regulating skin and hair development [ 42 – 44 ], these phenotypes may be associated with abnormal Wnt signalling which we have shown is regulated by PAWS1 [ 37 ].…”

Section: The Role Of Fam83g In Cell Signalling Morphology and Diseasmentioning

confidence: 99%

The FAM83 family of proteins: from pseudo-PLDs to anchors for CK1 isoforms

Bozatzi

Sapkota

2018

Biochemical Society Transactions

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The eight members of the FAM83 (FAMily with sequence similarity 83) family of poorly characterised proteins are only present in vertebrates and are defined by the presence of the conserved DUF1669 domain of unknown function at their N-termini. The DUF1669 domain consists of a conserved phospholipase D (PLD)-like catalytic motif. However, the FAM83 proteins display no PLD catalytic (PLDc) activity, and the pseudo-PLDc motif present in each FAM83 member lacks the crucial elements of the native PLDc motif. In the absence of catalytic activity, it is likely that the DUF1669 domain has evolved to espouse novel function(s) in biology. Recent studies have indicated that the DUF1669 domain mediates the interaction with different isoforms of the CK1 (casein kinase 1) family of Ser/Thr protein kinases. In turn, different FAM83 proteins, which exhibit unique amino acid sequences outside the DUF1669 domain, deliver CK1 isoforms to unique subcellular compartments. One of the first protein kinases to be discovered, the CK1 isoforms are thought to be constitutively active and are known to control a plethora of biological processes. Yet, their regulation of kinase activity, substrate selectivity and subcellular localisation has remained a mystery. The emerging evidence now supports a central role for the DUF1669 domain, and the FAM83 proteins, in the regulation of CK1 biology.

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“…Furthermore, outside of ESS, there have been no breed-specific analyses. Considering that different WGS efforts in dogs have recently proven to be advantageous in elucidating genetic susceptibility to disease [22][23][24][25][26][27], differences in body types [28], as well as adaptions against parasites [29], we have compiled and processed WGS data to begin the exploration of breed-specific CMT-risk alleles and, in this initial report, to specifically reveal the coding variants detected in orthologs of the high-risk human breast cancer susceptibility genes.…”

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing for the investigation of canine mammary tumor inheritance - an initial assessment of high-risk breast cancer genes reveal BRCA2 and STK11 variants potentially associated with risk in purebred dogs

Huskey

Goebel

Lloveras-Fuentes

et al. 2020

Canine Genet Epidemiol

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Background: Although, in general, cancer is considered a multifactorial disease, clustering of particular cancers in pedigrees suggests a genetic predisposition and could explain why some dog breeds appear to have an increased risk of certain cancers. To our knowledge, there have been no published reports of whole genome sequencing to investigate inherited canine mammary tumor (CMT) risk, and with little known about CMT genetic susceptibility, we carried out whole genome sequencing on 14 purebred dogs diagnosed with mammary tumors from four breedspecific pedigrees. Following sequencing, each dog's data was processed through a bioinformatics pipeline. This initial report highlights variants in orthologs of human breast cancer susceptibility genes. Results: The overall whole genome and exome coverage averages were 26.0X and 25.6X, respectively, with 96.1% of the genome and 96.7% of the exome covered at least 10X. Of the average 7.9 million variants per dog, initial analyses involved surveying variants in orthologs of human breast cancer susceptibility genes, BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53, and identified 19 unique coding variants that were validated through PCR and Sanger sequencing. Statistical analyses identified variants in BRCA2 and STK11 that appear to be associated with CMT, and breed-specific analyses revealed the breeds at the highest risk. Several additional BRCA2 variants showed trends toward significance, but have conflicting interpretations of pathogenicity, and correspond to variants of unknown significance in humans, which require further investigation. Variants in other genes were noted but did not appear to be associated with disease.

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Whole-Genome Sequencing of a Canine Family Trio Reveals a FAM83G Variant Associated with Hereditary Footpad Hyperkeratosis

Cited by 20 publications

References 49 publications

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

The FAM83 family of proteins: from pseudo-PLDs to anchors for CK1 isoforms

Whole genome sequencing for the investigation of canine mammary tumor inheritance - an initial assessment of high-risk breast cancer genes reveal BRCA2 and STK11 variants potentially associated with risk in purebred dogs

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