A single base deletion in the <i><scp>SLC</scp>45A2</i> gene in a Bullmastiff with oculocutaneous albinism

Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya; Leeb, Tosso

doi:10.1111/age.12582

Cited by 16 publications

(6 citation statements)

References 15 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: 92%

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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: 92%

“…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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“…membrane associated transporter protein, MATP or antigen isolated from immuno-selected melanoma-1, AIM1) (Newton et al, 2001). Mutations in the homologous gene underlie pigment dilution in a number of vertebrate species, including gorilla, several breeds of dog, tigers, horses, mice, shrew, chickens, pigeons, quail, frogs, fish and perhaps cattle (Caduff et al, 2017;DeLay et al, 2018;Domyan et al, 2014;Dooley et al, 2013;Fukamachi et al, 2001;Gunnarsson et al, 2007;Mariat et al, 2003;Minvielle et al, 2009;Newton et al, 2001;Prado-Martinez et al, 2013;Rothammer et al, 2017;Tsetskhladze et al, 2012;Tsuboi et al, 2009;Wijesena & Schmutz, 2015;Winkler et al, 2014;Xu et al, 2013), and polymorphisms at the SLC45A2 locus are associated with skin tone differences and skin aging in several human population studies (Adhikari et al, 2019;Branicki et al, 2008;Cerqueira et al, 2014;Fracasso et al, 2017;Han et al, 2008;Jonnalagadda et al, 2016;Law et al, 2017;Liu et al, 2015;Lopez et al, 2014;Soejima & Koda, 2007;Stokowski et al, 2007;Yuasa et al, 2006). OCA4 patients have very low levels of pigmentation and phenotypically resemble OCA2 patients who lack the melanosomal chloride channel, OCA2 (Bellono et al, 2014), suggesting that SLC45A2 plays an important role in melanogenesis (Montoliu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

Escobar

et al. 2020

MBoC

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SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type IV (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with those expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes, SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic variant. Our data suggest that SLC45A2 maintains melanosome neutralization initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.

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“…White coat color is a common color in dogs caused by at least two underlying distinct genetic mechanisms: the absence of melanocytes in the skin/hair or the absence of pigment in the melanocytes or hairs. In dogs, true albinism is rare and is due to SLC45A2 or OCA2 mutations [1,2,3,4]. The absence of melanocytes in the skin, also called piebaldism or leucism, is a variable phenotype ranging from white spots to more extreme white patterns, resulting in almost-white coat color with few pigmented areas.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs

Hédan

Cadieu

Botherel

et al. 2019

Genes

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White coat color in mammals has been selected several times during the domestication process. Numerous dog breeds are fixed for one form of white coat color that involves darkly pigmented skin. The genetic basis of this color, due to the absence of pigment in the hairs, was suggested to correspond to extreme dilution of the phaeomelanin, by both the expression of only phaeomelanin (locus E) and its extreme dilution (locus I). To go further, we performed genome-wide association studies (GWAS) using a multiple breed approach. The first GWAS, using 34 white dogs and 128 non-white dogs, including White Shepherds, Poodles, Cotons de Tulear and Bichons allowed us to identify two significantly associated loci on the locus E and a novel locus on chromosome 20. A second GWAS using 15 other breeds presenting extreme phaeomelanin dilution confirmed the position of locus I on the chromosome 20 (position 55 Mb pcorrected = 6 × 10−13). Using whole-genome sequencing, we identified a missense variant in the first exon of MFSD12, a gene recently identified to be involved in human, mouse and horse pigmentation. We confirmed the role of this variant in phaeomelanin dilution of numerous canine breeds, and the conserved role of MFSD12 in mammalian pigmentation.

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A single base deletion in the SLC45A2 gene in a Bullmastiff with oculocutaneous albinism

Cited by 16 publications

References 15 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

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs

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