J. lnher. Metab. Dis. 14 (1991) 189--201 © SSIEM and KluwerAcademicPublishers. Printed in the Netherlands Phenotypic Variability and Abnormal Type I Collagen Unstable at Body Temperature in a Family with Mild Dominant Osteogenesis Imperfecta R. TENNI 1, P. BIGLINO 2, K. DYNE 1, A. ROSS~ 1, M. FILOCAMO 3, F. PENDOLA 2, P. BRUNELLI 4, P. BUTTITTA 5, C. BORRONE 2 and G. CETTA ~ 1Centro per lo Studio delle Malattie del Tessuto Connettivo, Dipartimento di Biochimica, University of Pavia, via Taramelli 3b, 27100 Pavia, Italy; 2H Divisione Pediatria and 3L aboratorio III Divisione Pediatria, Istituto 'G. Gaslini', 16148 Genova, Italy; 40spedale dei Bambini, Ortopedia, 25100 Brescia, Italy; 50spedale dei Bambini 'G. Di Cristina', Divisione Neonatologia, 90134 Palermo, Italy Summary: Autosomal dominant inheritance of a mild form of osteogenesis imperfecta (osteogenesis imperfecta type I) with different phenotypic expression was found in a family. Phenotypic expression was different for the affected mother and son, in the presence of the same biochemical results. Dermal fibroblast cultures synthesized normal and mutant type I collagen chains. Collagen heterotrimers containing abnormal chains were overmodified along the entire triple helical domain and showed an unusually low denaturation temperature, so far found only in lethal cases. The mild phenotype in the family is probably due to the fact that abnormal type I collagen molecules are more likely to be degraded than utilized in the extracellular matrix. INTRODUCTION Osteogenesis imperfecta is a heterogeneous group of heritable disorders of connective tissue characterized by bone fragility in variable combination with other symptoms such as blue sclerae, dentinogenesis imperfecta and hypoacusia. On the basis of clinical, radiological and genetic data, Sillence and colleagues (1979) and Sillence (1988) proposed the classification of osteogenesis imperfecta into four types. The current classification of osteogenesis imperfecta, based on clinical and radiological changes, was devised by a group of experts in a workshop held during the 7th International Congress on Human Genetics, Berlin, 1986 (Beighton et al., 1988a). However, the heterogeneity of osteogenesis imperfecta far exceeds the number of subtypes considered in this classification, and classification for many patients is difficult (Beighton et al., 1988b). Furthermore, variability of phenotypic expression within the same affected family has also been reported (Beighton, 1981; de Vries and MS received 18.6.90 Accepted 29.8.90 189