title: Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis.
abstract: Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Oonagh
authors.initials: O
authors.lastname: Dowling
authors.forename: Analisa
authors.initials: A
authors.lastname: Difeo
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ramirez
authors.forename: Turgut
authors.initials: T
authors.lastname: Tukel
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafe
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Memnune
authors.initials: M
authors.lastname: Yuksel-Apak
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Karen
authors.initials: K
authors.lastname: Norton
authors.forename: Ahmad S
authors.initials: AS
authors.lastname: Teebi
authors.forename: Valerie
authors.initials: V
authors.lastname: Grum-Tokars
authors.forename: Gail S
authors.initials: GS
authors.lastname: Martin
authors.forename: George E
authors.initials: GE
authors.lastname: Davis
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002874:Chromosome Mapping; D005091:Exons; D005260:Female; D005350:Fibroma / Q000235:genetics*; D005808:Genes, Recessive; D005819:Genetic Markers; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018000:Receptors, Peptide; D013577:Syndrome
chemical_list: C447150:ANTXR2 protein, human; D005819:Genetic Markers; D008565:Membrane Proteins; D018000:Receptors, Peptide