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Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

ABSTRACT: Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

SUBMITTER: Hanks S

PROVIDER: S-EPMC1180602 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Hanks Sandra S Adams Sarah S Douglas Jenny J Arbour Laura L Atherton David J DJ Balci Sevim S Bode Harald H Campbell Mary E ME Feingold Murray M Keser Gökhan G Kleijer Wim W Mancini Grazia G McGrath John A JA Muntoni Francesco F Nanda Arti A Teare M Dawn MD Warman Matthew M Pope F Michael FM Superti-Furga Andrea A Futreal P Andrew PA Rahman Nazneen N

American journal of human genetics 20030821 4

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capi ...[more]

PMID: 14508707

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Project description:INTRODUCTION:Infantile Systemic Hyalinosis (ISH) is a rare and fatal genetic disorder with mutations in Capillary morphogenesis gene-2 CMG2 / Human anthrax toxin receptor gene-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism with extensive deposition of amorphous eosinophilic PAS positive hyaline material in the connective tissues of various organs. The common presenting features would be progressive stiffness of multiple joints, skin lesions, multiple episodes of protracted infections, prolonged diarrhoea and failure to thrive. ISH is a rapidly progressive painful disorder of infancy with a very short life expectancy. CASE PRESENTATION:3 months old identical twins born to a 5th degree consanguinous couple were brought with complaints of excessive cry, deformity of all four limbs, recurrent episodes of respiratory tract infections and diarrhoea since birth. Evaluation of both the probands revealed facial dysmorphism with perinasal nodules, gingival hypertrophy, fixed deformities of multiple joints bilaterally, umbilical hernia, fleshy perianal nodules and pigmented patches over knuckles and ankle. A clinical diagnosis of ISH was suspected and confirmed by detection of homozygous c.277_278insATTATTT (or p.L93Yfs*14) in exon 3 of the ANTXR2 gene. The probands were managed symptomatically and parents were counselled regarding prenatal diagnosis in future pregnancies. CONCLUSION:IHS is commonly misdiagnosed as Arthrogryposis Multiplex Congenita and is often mismanaged with manipulation of the stiff joints and invasive surgical procedures. Prenatal diagnosis by chorionic villus biopsy is possible once causative mutation in a family is identified. Invasive surgical interventions for histopathological analysis can be avoided as clinical features are most often classical and genetic analysis is confirmatory. Management is conservative and symptomatic. We report this case of identical twins with features of ISH in view of its rarity as timely clinical suspicion can avoid painful and invasive procedures for diagnosis and management.

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Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Publications

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

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