A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII

Abstract

Hundreds of different human skeletal disorders have been characterized at molecular level and a growing number of resembling dysplasias with orthologous genetic defects are being reported in dogs. This study describes a novel genetic defect in the Brazilian Terrier breed causing a congenital skeletal dysplasia. Affected puppies presented severe skeletal deformities observable within the first month of life. Clinical characterization using radiographic and histological methods identified delayed ossification and spondyloepiphyseal dysplasia. Pedigree analysis suggested an autosomal recessive disorder, and we performed a genome-wide association study to map the disease locus using Illumina’s 22K SNP chip arrays in seven cases and eleven controls. A single association was observed near the centromeric end of chromosome 6 with a genome-wide significance after permutation (p genome = 0.033). The affected dogs shared a 13-Mb homozygous region including over 200 genes. A targeted next-generation sequencing of the entire locus revealed a fully segregating missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB). The mutation was confirmed in a population of 202 Brazilian terriers (p = 7,71×10 −29 ). GUSB defects cause mucopolysaccharidosis VII (MPS VII) in several species and define the skeletal syndrome in Brazilian Terriers. Our results provide new information about the correlation of the GUSB genotype to phenotype and establish a novel canine model for MPS VII. Currently, MPS VII lacks an efficient treatment and this model could be utilized for the development and validation of therapeutic methods for better treatment of MPS VII patients. Finally, since almost one third of the Brazilian terrier population carries the mutation, breeders will benefit from a genetic test to eradicate the detrimental disease from the breed.

Mucopolysaccharidosis VII: A case report and literature review

“…Mutation of β-glucuronidase gene (GUSB MIM # 611499) have been described in many species including human, mouse, cat and dog [7,21]. To this date, forty-nine unique disease-causing mutations (missense mutations, deletions, nonsense mutations, splice-site mutations) in GUSB have been identified in person with MPS VII from various populations.…”

“…This was a landmark discovery of the crystal structure of human GUSB in the area of lysosomal targeting [23]. This high-resolution crystal structure of GUSB provided a precise mechanism for lysosomal targeting [21].…”

“…The β-glucuronidase is a lysosomal homotetramer [21], and comprised of 651 amino acid residues (78 kD) [22]. The GUSB monomer is comprised of three distinct structural domains.…”

Mucopolissacaridose em um cão: relato de caso

“…As alterações radiográficas incluem um conjunto de alterações esqueléticas, conhecidas por disostose multiplex, na qual os ossos são mais curtos, há erosão articular focal, efusão articular, subluxação de cotovelos e erosões nas epífises de todos os corpos vertebrais (Arias et al, 2011), má formação das cabeças umerais e suas respectivas cavidades glenoides, além de deformidades nos arcos costais, hepatomegalia, hipoplasia traqueal (Schultheiss et al, 2000;Dombrowski et al, 2004;Hytönen et al, 2012;Pérez et al, 2015).…”

“…Neste caso, os condrócitos revelaram citoplasma com diversos vacúolos (aspecto de células "claras") visualizados nas colorações de PAS e alcian blue. Hytönen et al (2012), estudaram os defeitos esqueléticos encontrados em cães da raça Fox Paulistinha (Terriers Brasileiros), e uma mutação no gene GUSB foi identificado. O cão do presente estudo era desta mesma raça, porém não foram feitos testes genéticos.…”