Background: Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by bone fragility. The current classification comprises five forms (OI types IV) with autosomal dominant inheritance and seven rarer forms (OI types VIXII) with recessive inheritance. OI type V (MIM 610967) has distinguishing radiological features, such as propensity to hyperplastic callus formation, calcification of the forearm interosseous membrane, radial-head dislocation, and a subphyseal metaphyseal radiodense line. The disease gene, coding for interferon-induced-transmembrane-protein-5 (IFITM5) has been identified very recently. A c.−14C>T recurrent mutation in its 5′UTR region has been found in 63 patients so far.
Case report: The 7-year-old male proband was diagnosed as affected by OI soon after birth because of a forearm fracture and classified as type V after age five because of pathognomonic radiological signs. Heterozygosity of the proband for the c.−14 C>T transition was revealed by direct sequencing of amplified patients genomic DNA obtained from a peripheral blood sample.
Methylation analysis: Total genomic DNA was extracted from cultured skin fibroblasts, leukocytes, sperm and bone marrow, from healthy male and female subjects. Sequence analysis of all samples revealed that c.−14C is 100% methylated in sperm and leukocytes while it appears ≥80% methylated in bone marrow and in fibroblasts.
Discussion: Unlike all other OI types, characterized by high genetic heterogeneity, OI type V appears consistently associated to a unique de novo C>T transition within the 5′UTR of IFITM5 gene.
Our data demonstrate that the recurrent de novo mutation causing type V OI involves deamination at a CpG dinucleotide which showed the lowest methylation levels, in the fibroblast DNA, in agreement with the connective tissues-specific expression of the gene, while is 100% methylated in male germ cells. We suggest that this recurrent base substitution may well represent a mutational hot spot in the human genome.
22 Jun 2013 - 25 Jun 2013