In other species: domestic cat , taurine cattle

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 607014 (trait) , 607015 (trait) , 607016 (trait) , 252800 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1992

Cross-species summary: Also known as Hurler syndrome

Species-specific name: Mucopolysaccharidosis I

Species-specific symbol: MPS I

Species-specific description: The mucopolysaccharidoses (MPS) are a group of hereditary diseases characterized by defective metabolism of glycosaminoglycans (mucopolysaccharides), which accumulate in lysosomes in various tissues.

History: In 1982 a family of Plott Hounds was recognized, in which three littermates were affected by MPS I. The clinical symptoms comprised growth retardation, joint problems, progressive lameness and visual impairment, caused by corneal clouding. Shull et al. provided a detailed pathological description (Shull et al. 1982). One of the affected dogs was used to establish a research colony, which was used over many years to evaluate treatment options for human MPS I. Vilander et al. (2019) diagnosed a Doberman Pinscher with MPS I via a urinary metabolic screen and serum enzyme activity tests. The dog was homozygous wild-type when tested for the known IDUA gene variants.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the same disorder in humans), Menon et al. (1992) showed the molecular basis for this disorder in Plott Hounds to be a "G>A transition in the donor splice site of intron 1" of the IDUA gene which encodes alpha-L-iduronidase. As explained by Menon et al. (1992), "The mutation causes retention of intron 1 in the RNA and creates a premature termination codon at the exon-intron junction." According to current nomenclature, the variant would be c.155+1G>A. Whole-genome sequencing by Mansour et al. (2020) of one affected Boston Terrier, followed by filtering of variants via a "bioinformatics pipeline . . . based on the expected mode of inheritance, against a database of canine variants, and according to their expected detrimental effect on the coding sequence" reduced the "initial 6,168,093 variants to only 10 homozygous mutations and 12 heterozygous mutations". Examination of these variants in relation to functional candidate genes led to the identification of a likely causal variant as " a frame-shift insertion affecting the alpha-L-iduronidase (IDUA) gene (c.19_20insCGGCCCCC)". This variant was subsequently identified in another affected Boston Terrier. (Mansour et al., 2020) Faller et al. (2020) reported "a novel homozygous deletion of 287 bp resulting in full deletion of exon 10 of the IDUA gene (NC_006585.3(NM_001313883.1):c.1400-76_1521+89del)" in affected animals in a family of Golden Retrievers.

Prevalence: Mansour et al. (2020): The likely insertion causal variant "was not detected in 120 unrelated Boston Terriers as well as 202 dogs from other breeds".

Breeds: Boston Terrier (Dog) (VBO_0200204), Doberman Pinscher (Dog) (VBO_0200442), Golden Retriever (Dog) (VBO_0200610), Plott Hound (Dog) (VBO_0201023).
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: