Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations

Abstract

Tissue-specific extracellular matrices (ECMs) are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited connective tissue disorders. Mutations cause ECM dysfunction by combinations of two mechanisms. First, secretion of the mutated ECM components can be reduced by mutations affecting synthesis or by structural mutations causing cellular retention and/or degradation. Second, secretion of mutant protein can disturb crucial ECM interactions, structure and stability. Moreover, recent experiments suggest that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, contributes to the molecular pathology. Targeting ER stress might offer a new therapeutic strategy.

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

“…It is widely accepted that, apart from the structural deficiencies, the pathology of different ECM disorders involves a broad spectrum of complex biological mechanisms, such as endoplasmic reticulum stress, dysregulated autophagy, or altered bioavailability of biologically active peptides and factors (42)(43)(44)(45)(46). Here, we demonstrate that this is also the case for RDEB.…”

Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population

“…9,10 Many fibrillar collagen genes have been implicated in a variety of human diseases; mutations in collagen type I are responsible for osteogenesis imperfecta (OI, MIM #166200), while mutations in genes for collagen type II, IX, X and XI can lead to a variety of chondrodysplasias. 11,12 COL27A1 encodes the pro-alpha chain of fibrillar collagen type XXVII. The gene is 156 kb in length, located on chromosome 9q32; it is formed by 61 exons and encodes a 1860-amino acid pro-peptide.…”

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

“…The diversity and functional importance of the ECM is illustrated by the occurrence of numerous genetic and acquired connective tissue disorders in which bone, cartilage, skin, muscle, brain, eye, and cardiovascular systems are differentially affected (5). In the present study, we demonstrate that TTD-specific mutations affecting the general TFIIH are responsible for the overexpression of MMP-1 gene in primary dermal fibroblasts and, in turn, for the loss of the interstitial component COL1 in the patient skin dermis.…”

“…Notably, the ECM is not only a structural scaffold but also exhibits important functional roles in controlling key cellular events (e.g., adhesion, migration, proliferation, differentiation, and survival) involved in tissue homeostasis, development, inflammation, and tissue repair (2,3). Thus, inherited or acquired structural alterations as well as metabolic disturbances of the ECM may cause cellular and tissue changes leading to the onset and progression of specific disorders, such as those affecting the connective tissues (osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan's syndrome) or demanding ECM degradation (tumor invasion and metastasis) (4,5). Recently, a reduced synthesis of the ECM component collagen type VI (COL6) was shown in confluent fibroblast cultures from patients with trichothiodystrophy [TTD; Online Mendelian Inheritance in Man (OMIM) #601675] (6), an autosomal recessive disorder characterized by symptoms affecting several tissues and organs (7).…”