In other species: domestic cat

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 253200 (trait) , 611542 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009661: mucopolysaccharidosis type 6

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2004

Cross-species summary: This disorder is a lysosomal storage disease, caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine 4-sulfatase.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in other species), Berman et al. (2004) were the first to report a molecular basis of this disorder, as follows: "When the DNA coding sequence from miniature pinschers affected with MPS VI was compared to the normal canine sequence, a single missense mutation (G to A) was identified. This mutation, occurring in exon V, replaces the tiny amino acid glycine with a bulky arginine in a highly conserved region of the protein and is found only in affected dogs." This result was finally published in a refereed paper by Raj et al. (2020). Jolly et al. (2012) reported a different mutation in a Miniature Poodle-type of dog: "A novel homozygous 22 base pair (bp) deletion in exon 1 of this enzyme's [ARSB] gene was identified (c.103_124del), which caused a frameshift and subsequent premature stop codon." Pérez et al. (2015) reported an affected Miniature Schnauzer homozygous for the same variant as reported by Berman et al. (2004). Wang et al. (2017) reported an affected Great Dane homozygous for a "nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis". Raj et al. (2020): "A missense variant (NM_001048133.1:c.910G>A) was found in exon 5 of MPS VI‐affected Miniature Pinschers that is predicted to result in a deleterious amino acid substitution of a highly conserved glycine to arginine (NP_001041598.1:p.Gly304Arg). In MPS VI‐affected Miniature Schnauzers, a 56 bp deletion (NM_001048133.1:c.‐24_32del) was found at the junction of exon 1 and its upstream region, predicting no enzyme synthesis. All clinically affected Miniature Pinschers and Miniature Schnauzers were homozygous for the respective variants, and screened healthy dogs in each breed were either heterozygous or homozygous for the wt allele."

Prevalence: Raj et al. (2020): "Over the past 17 years, a total of 425 Miniature Pinschers and two mixed‐breed dogs from the USA, Canada and UK were genotyped; of them 18 (4.2%) were homozygous for the missense variant [c.910G>A], including two mixed‐breed dogs, 78 (18.3%) were heterozygous and 331 (77.5%) were homozygous for the wt allele. All of the genotyped Miniature Pinschers that had clinical signs consistent with MPS VI were homozygous for the missense variant. . . . Whereas the Miniature Pinscher variant seemed to occur commonly (0.133 allele frequency), the Miniature Schnauzer variant was presumed to be rare"

Breeds: Chesapeake Bay Retriever (Dog) (VBO_0200326), Great Dane (Dog) (VBO_0200623), Miniature Pinscher (Dog) (VBO_0200893), Miniature Schnauzer (Dog) (VBO_0200896), Poodle, Miniature (Dog) (VBO_0201051), Poodle, Toy (Dog) (VBO_0201061), Welsh Corgi (Dog) (VBO_0201406).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: