Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Abstract

COL4A1 and COL4A2 are extracellular matrix proteins that form heterotrimers and are present in nearly all basement membranes in every organ. In the past decade, COL4A1 and COL4A2 mutations have been identified to cause a multi-system disorder for which penetrance and severity of constituent phenotypes can greatly vary. Here, we compare the outcomes of more than 100 mutations identified in patients and data from a murine allelic series to explore the presence of genotype-phenotype correlations – many of which are shared among other types of collagen. We find that there is a frequency bias for COL4A1 over COL4A2 mutations and that glycine (Gly) substitutions within the triple helical domain are the most common class of mutations. Glycine is most often replaced by a charged amino acid, however the position of the mutation, and not the properties of the substituting amino acid, appear to have a greater influence on disease severity. Moreover, the impact of position is not straightforward. Observations from a murine allelic series suggest that mutations in the NC1 domain may result in relatively mild phenotypes via a ‘quantitative’ mechanism similar to other types of collagens, however, this effect was not apparent in human reports. Importantly, other position-dependent effects had differential impacts depending on the phenotype of interest. For example, the severity of cerebrovascular disease correlated with an amino-to-carboxy severity gradient for triple-helical glycine substitutions whereas the penetrance and severity of myopathy and nephropathy appear to involve a functional sub-domain(s). Greater understanding of genotype-phenotype correlations and the interaction of consequences of different mutations will be important for patient prognosis and care and for developing mechanism-based therapeutics to treat individual components of this emerging syndrome.

Genome‐wide meta‐analysis identifies 3 novel loci associated with stroke

“…Collagen type IV α1 is a major constituent of the vascular basement membrane and forms heterotrimers with collagen IV α2. Rare variants in COL4A1 cause monogenic small vessel disease, with hemorrhagic and ischemic stroke being part of the spectrum . These mutations are associated with structural protein changes or altered expression levels of COL4A1, which interfere with the assembly, secretion, or biological function of COL4A1.…”

COL4A1 Mutations Cause Neuromuscular Disease with Tissue-Specific Mechanistic Heterogeneity

“…Mutations in genes coding for collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) chains cause a multisystem disorder that is generally characterized by the presence of cerebrovascular disease with variable ocular, renal, and muscular involvement (MIM: 607595, 614519, 175780). [1][2][3] Athough most studies have focused on cerebrovascular manifestations, many aspects of the COL4A1/A2 syndrome are still emerging and remain understudied. For instance, despite the fact that muscle pathology has been reported in up to one-third of individuals with COL4A1 (MIM: 120130) and COL4A2 (MIM: 120090) mutations 1 and in animal models (mice, C. elegans, and Drosophila) with mutations in COL4A1 and COL4A2 orthologs, [4][5][6][7][8][9] virtually nothing is known about the pathogenic mechanisms underlying COL4A1and COL4A2-related myopathy.…”

Building collagen IV smart scaffolds on the outside of cells

“…For example, the α3(IV), α4(IV), and α5(IV) chains are present in the glomerular basement membrane of the kidney and in the BM of lung, testis, and eye, whereas the α5(IV) and α6(IV) chains are found in the BM of skin, smooth muscle, and the kidney . Most mutations in COL4A1 and COL4A2, the genes encoding α1(IV) or α2(IV), respectively, cause multisystem disorders with heterogeneous pathogenic mechanisms and often lead to embryonic lethality . Mutations in COL4A3, COL4A4, and COL4A5, the genes encoding α3(IV), α4(IV), or α5(IV) chains, respectively, lead to renal failure and deafness in adult patients with Alport's syndrome …”

“…9 Most mutations in COL4A1 and COL4A2, the genes encoding a1(IV) or a2(IV), respectively, cause multisystem disorders with heterogeneous pathogenic mechanisms and often lead to embryonic lethality. [10][11][12][13][14] Mutations in COL4A3, COL4A4, and COL4A5, the genes encoding a3(IV), a4(IV), or a5(IV) chains, respectively, lead to renal failure and deafness in adult patients with Alport's syndrome. 15,16 Once secreted into the extracellular space, the triple-helical protomers self-associate to form distinct networks providing a molecular scaffold for interactions between other BM components such as laminin networks, perlecans, and proteoglycans to form a mature BM.…”