Lack of correlation between the type ofCOL1A1orCOL1A2mutation and hearing loss in osteogenesis imperfecta patients

Abstract

Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.

New perspectives on osteogenesis imperfecta

“…All OI types had hearing loss (approximately 60%, 80% and 40% of OI types I, III and IV, respectively). Further analysis of the Finnish OI population showed no correlation of hearing loss with collagen mutation type (null allele, glycine substitution or splicing defect) or mutated collagen gene, as well as a lack of penetrance in some family members 132 . About half of Finnish OI adults also have vestibular dysfunction, with vertigo generally secondary to inner ear pathology 133 .…”

Gene expression profile analysis of human intervertebral disc degeneration

“…COL1A2 is a protein found in most connective tissues. Mutations in this gene are associated with asteo-genesis imperfecta, Ehlers-Danlos syndrome, idiopathic osteoporosis and atypical Marfan syndrome (Vasan et al , 1991; Ward et al , 2001; Hartikka et al , 2004). However, the symptoms associated with mutations in this gene tend to be less severe than with mutations in the gene for α1 type I collagen since the α2 form is less abundant (Bou-Gharios et al , 2004).…”

Genotype-Phenotype Correlations in Autosomal Dominant Osteogenesis Imperfecta

“…In one study on adults with OI, 60% of patients with glycine substitutions and 70% of patients with haploinsufficiency mutations had hearing loss [24]. The different mutations resulted in overlapping hearing phenotypes and there was a marked intrafamilial variability in hearing phenotype between family members with the same mutation.…”