Characterization of α1(IV) Collagen Mutations in <i>Caenorhabditis elegans</i> and the Effects of α1 and α2(IV) Mutations on Type IV Collagen Distribution

Gupta, Malini C.; Graham, Patricia L.; Kramer, James M.

doi:10.1083/jcb.137.5.1185

Cited by 115 publications

(120 citation statements)

References 48 publications

(84 reference statements)

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“…In these animals, type IV collagen is reduced or absent from basement membranes, but is correspondingly seen to accumulate within the cells that synthesize it, possibly because of the high rate of ␣1(IV) to ␣2(IV) chain synthesis during development. 63 Using the immunofluorescence amplification technique and antibodies directed against the NC1 domain of the chain, we have been able to demonstrate for the first time the presence of the ␣3(IV) protein within human AS podocytes, a finding very special to AS patients, not seen in normal kidneys, and exceptional in other pathological conditions. The presence of both the transcripts and the protein indicate that the loss of the ␣3(IV) chain in Xlinked AS GBM results from events downstream of transcription, RNA processing, and protein synthesis.…”

Section: Discussionmentioning

confidence: 84%

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the ␣5 chains of type IV collagen in basement membranes. This is associated with the absence of the ␣3(IV) and ␣4(IV) chains and increased amounts of ␣1(IV) and ␣2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the ␣3 chain of type IV collagen was present in the podocytes of all patients. Finally, the ␣1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of ␣3(IV) to ␣5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

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Section: Discussionmentioning

confidence: 84%

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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“…Shifting to 25°C resulted in severe gonadal defects, which precluded the analysis of mig-17 suppression. To examine whether reduction of type IV collagen in the BM affects the suppression, we depleted a single copy of emb-9/␣1 chain of type IV collagen using the null allele emb-9(g23cg46) (13). We found that g23cg46/ϩ partially suppressed mig-17(k174) (Fig.…”

Section: Resultsmentioning

confidence: 99%

MIG-17/ADAMTS controls cell migration by recruiting nidogen to the basement membrane in C. elegans

Kubota¹,

Ohkura

Tamai

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family of secreted proteases cause diseases linked to ECM abnormalities. However, the mechanisms by which these enzymes modulate the ECM during development are mostly unexplored. The Caenorhabditis elegans MIG-17/AD-AMTS protein is secreted from body wall muscle cells and localizes to the basement membrane (BM) of the developing gonad where it controls directional migration of gonadal leader cells. Here we show that specific amino acid changes in the ECM proteins fibulin-1C (FBL-1C) and type IV collagen (LET-2) result in bypass of the requirement for MIG-17 activity in gonadal leader cell migration in a nidogen (NID-1)-dependent and -independent manner, respectively. The MIG-17, FBL-1C and LET-2 activities are required for proper accumulation of NID-1 at the gonadal BM. However, mutant FBL-1C or LET-2 in the absence of MIG-17 promotes NID-1 localization. Furthermore, overexpression of NID-1 in mig-17 mutants substantially rescues leader cell migration defects. These results suggest that functional interactions among BM molecules are important for MIG-17 control of gonadal leader cell migration. We propose that FBL-1C and LET-2 act downstream of MIG-17-dependent proteolysis to recruit NID-1 and that LET-2 also activates a NID-1-independent pathway, thereby inducing the remodeling of the BM required for directional control of leader cell migration.ECM ͉ fibulin-1 ͉ organogenesis ͉ type IV collagen T he interaction between basement membranes (BMs) and migrating cells or the epithelial layer is a complicated but carefully controlled process that involves remodeling of the ECM. For example, the migration of border cells required for oogenesis and patterning of the early embryo in Drosophila melanogaster is accompanied by precise regulation of the synthesis and degradation of type IV collagen, laminin, and perlecan (1, 2). Fibronectin expression is required for branching morphogenesis of the submandibular salivary gland, lung, and kidney in mouse (3). However, the mechanisms of cell-ECM interactions and the roles of BMs in cell migration remain largely unknown.Gonadogenesis in the nematode Caenorhabditis elegans serves as a simple model system for elucidating the function of BMs in organ morphogenesis. The development of hermaphrodite gonads is regulated by the migration of gonadal distal tip cells (DTCs), which promote directional elongation of the gonad arms during the larval stages to form the U-shaped gonads found in adult animals (4, 5). Two secreted a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family metalloproteases, MIG-17 and GON-1, are involved in this process. GON-1 is required for DTC motility, whereas MIG-17 controls the direction of DTC movement but does not control DTC motility per se (6, 7). MIG-17 is expressed in the body wall muscles and is localized to the BM of the gonad surface, where it is required for DTC migration (7,8). It has been proposed that MIG-17 and GON-1 remodel BMs via prote...

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“…Heterozygote truncating mutations have already been observed in collagen IV-related Alport syndrome, but null alleles for the C. elegans COL4A1 homologue, emb-9 and COL4A2 homologue let2 cause disruption of the basement membrane and embryonic lethality, although at a later stage than the G-Xaa-Yaa missense mutations. 28 The non-collagen domain of collagen IV alpha-2, but not alpha-1 chain, promotes cell adhesion, outgrowth of embryonic neurons and is responsible for strict regulation of the 2:1 stoichiometry of the triple helix. 18,[29][30][31] This could indicate that a disturbed ratio of procollagen alpha-1 and procollagen alpha-2 chains due to a heterozygous null allele of either COL4A1 or COL4A2 may lead to a disturbed or insufficient heterotrimer assembly and secretion.…”

Section: Pathogenesis Of Col4a2 Mutationsmentioning

confidence: 99%

COL4A2 mutation associated with familial porencephaly and small-vessel disease

et al. 2012

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Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 3206delC fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

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Characterization of α1(IV) Collagen Mutations in Caenorhabditis elegans and the Effects of α1 and α2(IV) Mutations on Type IV Collagen Distribution

Cited by 115 publications

References 48 publications

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

MIG-17/ADAMTS controls cell migration by recruiting nidogen to the basement membrane in C. elegans

COL4A2 mutation associated with familial porencephaly and small-vessel disease

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