Mutations in collagen 18A1 (COL18A1) and their relevance to the human phenotype

Abstract

Collagen XVIII, a proteoglycan, is a component of basement membranes (BMs). There are three distinct isoforms that differ only by their N-terminal, but with a specific pattern of tissue and developmental expression. Cleavage of its C-terminal produces endostatin, an inhibitor of angiogenesis. In its N-terminal, there is a frizzled motif which seems to be involved in Wnt signaling. Mutations in this gene cause Knobloch syndrome (KS), an autosomal recessive disorder characterized by vitreoretinal and macular degeneration and occipital encephalocele. This review discusses the effect of both rare and polymorphic alleles in the human phenotype, showing that deficiency of one of the collagen XVIII isoforms is sufficient to cause KS and that null alleles causing deficiency of all collagen XVIII isoforms are associated with a more severe ocular defect. This review besides illustrating the functional importance of collagen XVIII in eye development and its structure maintenance throughout life, it also shows its role in other tissues and organs, such as nervous system and kidney.

The multiple functions of collagen XVIII in development and disease

“…In most cases all the variants of collagen XVIII are affected, but one known mutation affects only the short isoform (Sertie et al, 2000;Suzuki et al, 2009). Knobloch syndrome is characterized by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele, which is a neural tube closure defect (Passos-Bueno et al, 2006; Table 1). A few cases with defects in neuronal migration, seen as heterotopic nodules in the brain, have been reported (Kliemann et al, 2003;Keren et al, 2007).…”

Lack of Collagen XVIII/Endostatin Exacerbates Immune-Mediated Glomerulonephritis

“…8,9 Inactivating mutations in the human gene for Col 18, COL18A1, have been identified in patients with Knobloch syndrome, which is an autosomal recessive disorder characterized by the occurrence of vitreoretinal degeneration with retinal detachment, high myopia, macular degeneration, occipital encephalocele, and minor renal abnormalities. 10,11 The kidney of Col 18/endostatin-null mice exhibits no abnormalities on light microscopy, where expansion of the mesangial matrix and thickened proximal tubular BM are observed on electron microscopy. 7,8 The study of Utriainen et al 8 suggested that Col 18/endostatin may have a role in maintaining the structural integrity of the extracellular matrix in the normal kidney, whereas its role in susceptibility and progression of inflammatory glomerular diseases remains to be clarified.…”

Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing

“…Mutations in the Col18A1 gene lead to Knobloch syndrome, characterised by several ocular defects and occipital encephalocele (Passos-Bueno et al, 2006). Lack of the C-terminal endostatin domain of the collagen XVIII homologue, cle-1 in C. elegans leads to defects in cell migration and axon guidance .…”