title: Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP.
abstract: We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Ana Belinda
authors.initials: AB
authors.lastname: Campos-Xavier
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.forename: Marisol
authors.initials: M
authors.lastname: Del Rosario
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Ute
authors.initials: U
authors.lastname: Knoll
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Mohandas
authors.initials: M
authors.lastname: Nair
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000595:Amino Acid Sequence; D001848:Bone Diseases, Developmental / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006056:Golgi Apparatus / Q000201:enzymology; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007592:Joint Diseases / Q000201:enzymology / Q000473:pathology*; D017880:Limb Deformities, Congenital / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D020836:Protein Structure, Quaternary; D011509:Proteoglycans / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism; D055815:Young Adult
chemical_list: D009711:Nucleotides; D011509:Proteoglycans; D015238:Sulfotransferases; D010744:Phosphoric Monoester Hydrolases