A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII
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{"title"=>"A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII", "type"=>"journal", "authors"=>[{"first_name"=>"Marjo K.", "last_name"=>"Hytönen", "scopus_author_id"=>"7003691505"}, {"first_name"=>"Meharji", "last_name"=>"Arumilli", "scopus_author_id"=>"55305701700"}, {"first_name"=>"Anu K.", "last_name"=>"Lappalainen", "scopus_author_id"=>"7004024167"}, {"first_name"=>"Heli", "last_name"=>"Kallio", "scopus_author_id"=>"57197388102"}, {"first_name"=>"Marjatta", "last_name"=>"Snellman", "scopus_author_id"=>"6701766690"}, {"first_name"=>"Kirsi", "last_name"=>"Sainio", "scopus_author_id"=>"7005860187"}, {"first_name"=>"Hannes", "last_name"=>"Lohi", "scopus_author_id"=>"6602309083"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22815736", "sgr"=>"84863622654", "doi"=>"10.1371/journal.pone.0040281", "scopus"=>"2-s2.0-84863622654", "pui"=>"365201744", "isbn"=>"1932-6203", "issn"=>"19326203"}, "id"=>"0c1ec399-68de-310a-93a2-597c81ea2c20", "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.", "link"=>"http://www.mendeley.com/research/novel-gusb-mutation-brazilian-terriers-severe-skeletal-abnormalities-defines-disease-mucopolysacchar", "reader_count"=>15, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Librarian"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>2, "Student > Master"=>4, "Other"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Librarian"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>2, "Student > Master"=>4, "Other"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>4, "Agricultural and Biological Sciences"=>6, "Social Sciences"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Social Sciences"=>{"Social Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Finland"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/614209"], "description"=>"<p>The activity of β-glucuronidase and α-mannosidase was measured from the serum samples of three affected, carrier and normal dogs. Activity is expressed as µmol/l/h.</p>", "links"=>[], "tags"=>["enzyme", "activities", "serum", "affected", "brazilian"], "article_id"=>284699, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.t002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lysosomal_enzyme_activities_in_the_serum_of_affected_and_healthy_Brazilian_Terriers_/284699", "title"=>"Lysosomal enzyme activities in the serum of affected and healthy Brazilian Terriers.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-07-05 01:18:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/320030", "https://ndownloader.figshare.com/files/320118", "https://ndownloader.figshare.com/files/320171"], "description"=>"<div><p>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<sub>genome</sub>  = 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<sup>−29</sup>). 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 <em>GUSB</em> 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.</p> </div>", "links"=>[], "tags"=>["mutation", "brazilian", "terriers", "skeletal", "abnormalities", "defines", "mucopolysaccharidosis", "vii"], "article_id"=>123180, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040281.s001", "https://dx.doi.org/10.1371/journal.pone.0040281.s002", "https://dx.doi.org/10.1371/journal.pone.0040281.s003"], "stats"=>{"downloads"=>10, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Novel_GUSB_Mutation_in_Brazilian_Terriers_with_Severe_Skeletal_Abnormalities_Defines_the_Disease_as_Mucopolysaccharidosis_VII/123180", "title"=>"A Novel <em>GUSB</em> Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-07-05 00:53:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/614100"], "description"=>"<p>A multiple alignment of the substitution site (P289) indicates a high conservation across taxa including eukaryotic and prokaryotic species. The p.P289L mutation is predicted to be pathogenic and likely disrupts the structure of the GUSB enzyme.</p>", "links"=>[], "tags"=>["mutation"], "article_id"=>284592, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.g005", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_conservation_of_the_GUSB_mutation_site_/284592", "title"=>"The conservation of the <i>GUSB</i> mutation site.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-05 01:16:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/613697"], "description"=>"<p>Comparison of the hind limbs of an affected 4-week-old puppy (A) and a healthy littermate (B) revealed epiphyseal dysplasia in the affected dog. The ossification centers of the epiphyses of the proximal tibia (long arrow) and tarsal bones (short arrow) are smaller in the affected puppy while the epiphyses of the healthy littermate are normally mineralized. The vertebral endplates of the lumbar spine (arrow) are poorly mineralized in the affected (C) puppy as compared with the healthy littermate (D). The skull of an affected 6-week-old Brazilian Terrier (E) has brachycephalic appearance with shortened maxilla. Radiopacity of the bones is reduced. The cervical vertebral endplates are not mineralized (arrow). A skull of a normal littermate is shown in comparison (F). Histological examination of the skeletal structures of a 4-week-old affected puppy showed normal growth plate with resting, proliferating and hypertrophic layers of chondrocytes in the tibia (G) but lack of secondary ossification center and occasional separate spots of loose fibrous tissue without sign of osteogenesis (I). The lack of secondary ossification centers and irregularities of the growth plate were present in the vertebral bodies (J). The epiphysis of a 5-week old healthy puppy is shown in comparison (H). Scale bar 100 µm.</p>", "links"=>[], "tags"=>["histological", "skeletal", "brazilian", "terrier"], "article_id"=>284188, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.g002", "stats"=>{"downloads"=>1, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Radiographic_and_histological_features_of_skeletal_disease_in_Brazilian_Terrier_puppies_/284188", "title"=>"Radiographic and histological features of skeletal disease in Brazilian Terrier puppies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-05 01:09:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/613378"], "description"=>"<p>Deformed legs with crooked radiocarpal joints and prominent joint hyperlaxity especially in the hind limbs (A) and a brachycephalic craniofacial morphology (C) presented by a 4-week-old Brazilian Terrier puppy compared to a healthy littermate (B,D). The affected puppies (n = 3) were severely growth retarded and weighted 35% less than their healthy littermates (n = 4) at the age of three weeks (E).</p>", "links"=>[], "tags"=>["affected", "brazilian"], "article_id"=>283865, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.g001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Morphological_features_of_the_affected_Brazilian_Terriers_/283865", "title"=>"Morphological features of the affected Brazilian Terriers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-05 01:04:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/613855"], "description"=>"<p>The pedigree with multiple affected dogs in the litters, equal gender distribution and healthy parents suggests a recessive mode of inheritance. Squares note males and circles females. Black-filling indicates affected dogs. Genotypes of the <i>GUSB</i> gene (T/T = homozygous mutation allele, C/C = homozygous wild type allele) are shown below the boxes. Dogs used in the NGS are marked by asterisks.</p>", "links"=>[], "tags"=>["brazilian", "terrier", "pedigree", "established", "affected"], "article_id"=>284343, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.g003", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_example_of_our_large_Brazilian_Terrier_pedigree_established_around_the_affected_puppies_/284343", "title"=>"An example of our large Brazilian Terrier pedigree established around the affected puppies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-05 01:12:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/614176"], "description"=>"<p>The 13,2-Mb locus at CFA6 was captured and sequenced in two cases and two controls with opposite haplotypes. Variants were discovered by comparing the target sequence with the reference sequence. Ensembl’s CanFam2.0 was used as a reference. The variants present only in the affected dogs were found by comparing the two Brazilian Terriers cases with the two breed controls and 32 other dogs from four breeds without any skeletal diseases.</p>", "links"=>[], "tags"=>["indel", "ngs", "locus", "brazilian"], "article_id"=>284664, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.t001", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNP_and_indel_statistics_of_the_NGS_of_the_identified_locus_in_Brazilian_Terriers_/284664", "title"=>"SNP and indel statistics of the NGS of the identified locus in Brazilian Terriers.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-07-05 01:17:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/613957"], "description"=>"<p>Manhattan plot indicates the best SNP with a raw and an empirical p-value after 100 000 permutations (A). Affected dogs share a 13-Mb homozygous haplotype, which contains over 200 genes (B). Colors in haplotype block are as follows: plum marks the homozygous allele, orange heterozygous allele and yellow an opposite homozygous allele. Dogs used for the NGS are marked by asterisks. A targeted sequencing of the entire locus identified a homozygous c.866C>T mutation in the exon 5 of the <i>GUSB</i> gene (C). The mutation was found by next generation sequencing (D) and was validated by Sanger sequencing (E).</p>", "links"=>[], "tags"=>["genome-wide", "reveals", "locus"], "article_id"=>284449, "categories"=>["Physiology", "Cell Biology", "Genetics"], "users"=>["Marjo K. Hytönen", "Meharji Arumilli", "Anu K. Lappalainen", "Heli Kallio", "Marjatta Snellman", "Kirsi Sainio", "Hannes Lohi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040281.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_genome_wide_association_study_reveals_an_associated_locus_at_CFA6_/284449", "title"=>"A genome-wide association study reveals an associated locus at CFA6.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-05 01:14:09"}

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Relative Metric

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