The phenotypic spectrum of COL2A1 mutations.

Abstract

Heterozygous mutations of COL2A1 create several clinical entities collectively termed type II collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-I), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1(II) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD-I to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype-phenotype relationship of type II collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in-frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice-site mutations in the triple helical or N-propeptide region caused STD-I or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes.

• Authors: Gen Nishimura, Nobuhiko Haga, Hiroshi Kitoh, Yoko Tanaka, Toru Sonoda, Miho Kitamura, Shuya Shirahama, Taichi Itoh, Eiji Nakashima, Hirofumi Ohashi, Shiro Ikegawa
• Journal: Human mutation (Hum Mutat) Vol. 26 Issue 1 Pg. 36-43 (Jul 2005) ISSN: 1098-1004 [Electronic] United States
• PMID: 15895462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL2A1 protein, human
• Collagen Type II

Topics

• Adolescent
• Adult
• Aged
• Child
• Child, Preschool
• Collagen Type II (chemistry, genetics, metabolism)
• Congenital Abnormalities (genetics)
• DNA Mutational Analysis
• Female
• Genotype
• Humans
• Infant
• Male
• Middle Aged
• Mutation (genetics)
• Phenotype
• Protein Conformation