Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis
Child; Female; Humans; Male; Mutation; P.H.S.; Research Support; U.S. Gov't; Syndrome; infant; Models; Pedigree; Membrane Proteins/genetics; Base Sequence; Amino Acid Sequence; Exons; Genes; Recessive; Missense; Molecular; Chromosome Mapping; Fibroma/genetics; Genetic Markers; Focal/genetics; Glomerulosclerosis; Protein Conformation; Protein Structure; Secondary
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.
2003
Dowling O; Difeo A; Ramirez MC; Tukel T; Narla G; Bonafe L; Kayserili H; Yuksel-Apak M; Paller AS; Norton K; Teebi AS; Grum-Tokars V; Martin GS; Davis GE; Glucksman MJ; Martignetti JA
American Journal Of Human Genetics
2003
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Journal Article
<a href="http://doi.org/10.1086/378781" target="_blank" rel="noreferrer">10.1086/378781</a>
Self-Reported Health Outcomes of Children and Youth with 10 Chronic Diseases
child; chronic disease; patient-reported outcomes; PROMIS
Objectives To identify pediatric patient-reported outcomes (PROs) that are associated with chronic conditions and to evaluate the effects of chronic disease activity on PROs. Study design Participants 8-24 years-old and their parents were enrolled into 14 studies that evaluated PROMIS® PROs across 10 chronic conditions--asthma, atopic dermatitis, cancer, cancer survivors, chronic kidney disease, Crohn’s disease, juvenile idiopathic arthritis, lupus, sickle cell disease, and type 1 diabetes mellitus. PRO scores were contrasted with the United States general population of children using nationally representative percentiles. PRO-specific coefficients of variation were computed to illustrate the degree of variation in scores within versus between conditions. Condition-specific measures of disease severity and Cohens d effect sizes were used to examine PRO scores by disease activity. Results Participants included 2,975 child respondents and 2,392 parent respondents who provided data for 3,409 unique children: 52% were 5-12 years-old, 52% female, 25% African-American/Black, and 14% Hispanic. Across all 10 chronic conditions, children reported more anxiety, fatigue, pain, and mobility restrictions than the general pediatric population. Variation in PRO scores within chronic disease cohorts was equivalent to variation within the general population, exceeding between-cohort variation by factors of 1.9 (mobility) to 5.7 (anxiety). Disease activity was consistently associated with poorer self-reported health, and these effects were weakest for peer relationships. Conclusions Chronic conditions are associated with symptoms and functional status in children and adolescents across 10 different disorders. These findings highlight the need to complement conventional clinical evaluations with those obtained directly from patients themselves using PROs.
Forrest CB; Schuchard J; Bruno C; Amaral S; Cox ED; Flynn KE; Hinds PS; Huang IC; Kappelman MD; Krishnan JA; Kumar RB; Lai JS; Paller AS; Phipatanakul W; Schanberg LE; Sumino K; Weitzman ER; Reeve BB
The Journal of Pediatrics
2022
<a href="http://doi.org/10.1016/j.jpeds.2022.02.052" target="_blank" rel="noreferrer noopener">10.1016/j.jpeds.2022.02.052</a>