Infantile systemic hyalinosis (ISH) is a rare, progressive autosomal recessive disease, which is usually fatal by the age of 2 years. Clinical onset typically occurs within the first few weeks of life. The disease is characterized by joint contractures, osteopenia, failure to thrive, gingival hypertrophy, diarrhea, protein-losing enteropathy, and frequent infections. Dermatologic manifestations include thickened skin, hyperpigmentation, perianal nodules, and facial papules. Histopathology shows hyaline deposits in the dermis and visceral organs. We describe a patient with ISH confirmed by clinical and histopathologic findings, as well as DNA sequence analysis, which revealed a novel homozygous T118K mutation in the CMG2 gene.
"Systemic involvement has been reported in severe cases and is usually associated with a fatal outcome. Infiltration of the small intestine and colon, the most common form of systemic involvement, leads to malabsorption and protein-losing enteropathy with diarrhea , failure to thrive, and an increased susceptibility to infection (Lindvall et al., 2008; Al-Mubarak et al., 2009). Other organs that may be affected include the heart, trachea, esophagus, stomach, spleen, adrenal glands, thyroid, lymph nodes, and skeletal muscle (Al-Mubarak et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Introduction: Farber lipogranulomatosis and infantile systemic hyalinosis are two rare autosomal recessive diseases with overlapping phenotypic features. Aim: The aim of the study was to present the difficulty in differentiating between these two rare disorders on clinical bases only and emphasize the importance of exome sequencing in the accurate diagnosis of patients with atypical presentations of known genetic diseases. Patients and methods: Two Egyptian cousins born to consanguineous parents presented with hoarseness of cry, painful swollen joint contractures, failure to thrive, diffuse thickening and hyperpigmentation of skin over bony prominences, and death before 2 years of age. Their initial differential diagnosis of Farber disease was ruled out because no pathogenic mutations were identified in the ASAH1 gene in either the proband or the parents. Accurate diagnosis in the affected was revealed as infantile systemic hyalinosis by exome sequencing, showing a homozygous pathogenic variant in the ANTXR2 gene. Conclusion: In the present work we highlight the need for molecular studies by next-generation sequencing for accurate diagnosis, prevention, and proper counseling when genetic diagnosis cannot be reached by other conventional methods.
"The C-terminally truncated CMG2 that is produced—at very low levels—is properly targeted to the plasma membrane (Liu et al, 2007) and thus would not trigger any UPR. Similarly, the p.T118K mutation, which was reported for a homozygous HFS patient (Lindvall et al, 2008) and is defective in ligand binding (Scobie & Young, 2006), does not show any folding defect and is not expected to trigger the UPR. Our strategy was therefore to attempt rescuing CMG2 from ERAD using proteasome inhibitors. "
[Show abstract][Hide abstract] ABSTRACT: Hyaline Fibromatosis Syndrome (HFS) is a human genetic disease caused by mutations in the anthrax toxin receptor 2 (or cmg2) gene, which encodes a membrane protein thought to be involved in the homeostasis of the extracellular matrix. Little is known about the structure and function of the protein or the genotype–phenotype relationship of the disease. Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level. Altogether, we show that missense mutations that map to the extracellular von Willebrand domain or the here characterized Ig-like domain of CMG2 lead to folding defects and thereby to retention of the mutated protein in the endoplasmic reticulum (ER). Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation. Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.
EMBO Molecular Medicine 04/2011; 3(4):208-21. DOI:10.1002/emmm.201100124 · 8.67 Impact Factor
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