A new culprit in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous group of heritable disorders affecting bone and connective tissue. It is most notably characterized by bone fragility, decreased bone mass, and recurrent fractures that can lead to skeletal deformities. The clinical severity can vary widely depending on the genetic mutation involved. The majority of individuals with OI have dominantly inherited mutations in either COL1A1 or COL1A2, which encode the a chains of type I collagen. In a minority of individuals with OI, however, the disease exhibits an autosomal recessive inheritance pattern. In most cases in which the affected genes have been identified, they have been found to encode proteins whose functions can be plausibly linked to the maturation and processing of collagen. For example, three of these genes encode components of the prolyl-3-hydroxylase complex, which can modify Pro986 in the a1 chains of type I collagen (CRTAP, LEPRE1, and PPIB), and two of these genes encode chaperones (SERPINH1 and FKBP10), which may be important for proper folding of procollagen (MIM #605497, #610339, #123841, #600943, #607063). Hence, the genetic data have thus far been consistent with the hypothesis that abnormalities in collagen biosynthesis and maturation are primarily responsible for the etiology of OI. Two recent papers by Becker et al. and Homan et al. (in this issue), however, have reported mutations in another gene, SERPINF1, which encodes pigment epithelium-derived factor (PEDF), whose link to collagen is less apparent, thereby raising the possibility of an alternative disease mechanism for OI. In the March issue of the American Journal of Human Genetics, Becker et al. reported the identification of three different truncating mutations in SERPINF1 in four individuals with autosomal recessive OI. Becker et al. initially focused on one patient whose parents were second cousins from the United Arab Emirates. Based on the consanguinity, the authors reasoned that the patient likely would be homozygous for the same mutation, and they carried out exome sequencing in order to identify the gene responsible. By applying a variety of statistical analyses, the authors homed in on one likely candidate gene, namely SERPINF1, in which they had identified a single nucleotide change predicted to cause a premature stop. This patient was homozygous for the point mutation, as was the patient’s affected brother (both parents and two unaffected sisters were heterozygous). The authors thenwent on to examine the SERPINF1 gene in other unrelated patients with similar clinical features and identified two additional truncating mutations in patients of Turkish descent with parental consanguinity. In the current issue of Journal of Bone and Mineral Research, Homan et al. independently report two additional SERPINF1 mutations, each predicted to cause premature stops. This group identified one of these homozygous mutations in members of a consanguineous French Canadian family and the other in an Italian patient, all of whom were classified as having OI type VI, a unique form of OI first described by Glorieux et al. in 2002. The investigators performed extensive homozygosity mapping and next-generation sequencing of the candidate gene region in order to identify SERPINF1 as the causative gene. OI type VI is clinically different from the other recessive forms in that the children do not fracture until approximately 6 months of age, unlike those with other recessive OI disorders who fracture at birth. Bone biopsy reveals a distinctive pattern; specifically, there are large amounts of osteoid devoid of mineralization and a ‘‘fish-scale pattern’’ of bone lamellation. Homan et al. provided histologic and bone biopsy data for their three patients; all revealed the characteristic excess of unmineralized osteoid typical of OI type VI, and one had the additional unique fish-scale appearance with abnormal lamellation. Biopsy data, however, were not provided by Becker et al. Of note is that patients with OI type VI are also unique in that their responses to cyclical pamidronate therapy result in less improvement in mobility and a lower reduction in fracture incidence than in patients with OI types I, III, and IV. The types of OI have expanded as the number of responsible identified genetic mutations has increased, thereby resulting in a system of classification that has become increasingly complex. This problem was addressed in the ‘‘Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision,’’ with the goal of basing the classification on clinical severity as per the original COMMENTARY JBMR