Autosomal Dominant Osteogenesis Imperfecta Research Articles

MON-493 A Unique Case of Severe Osteogenesis Imperfecta Due to a Novel Heterozygous Mutation in COL1A1 Gene with Overlapping Hypophosphatasia Phenotype

Background: Osteogenesis imperfecta (OI) is a rare heterogeneous bone fragility disease due to collagen defect most often caused by autosomal dominant (AD) COL1A1 or COL1A2 gene mutations. Severe forms of Hypophosphatasia (HPP) may phenotypically resemble OI, is a distinct disorder of hypomineralization caused by the mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Here in, we present the first case of a neonate with severe perinatal OI caused by a novel AD mutation in COL1A1 gene with HPP phenotype treated with asfotase alfa. Case: A 3-day-old full-term boy born by cesarean section presented with multiple fractures & dislocated hips at birth. On physical exam, he was found to have respiratory distress ultimately requiring intubation, hypoplastic rib-cage, blue sclerae, mesomelia, rhizomelia, left & right dislocated hips. Skeletal survey showed multiple fractures of long bones and ribs of varying ages, characteristic of OI. In addition, he was noted to have generalized hypomineralization, hypoplastic ribs, and some metaphyseal flaring. Interestingly, biochemical evaluation revealed hypercalcemia (corrected calcium of 11.7 mg/dL), low alkaline phosphatase (ALP) 58(80-270 U/L), slightly elevated pyridoxal 5” phosphate 52 (5-50 mg/dL) & high urine phosphoethanolamine 285(83-222 mcmol/g Cr). Due to clinical, radiographic, and biochemical findings concerning for HPP, the patient was started on asfotase alfa. The genetic testing showed a novel likely pathogenic heterozygous variant Chr17: c.1201G>C (p.Gly401Arg) in the COL1A1 gene consistent with AD OI. The ALPL gene sequencing revealed no variants in the coding region with 100% coverage of the region. After 7 wks of treatment, x-rays showed two new long bone fractures, but interval osseous remodeling & healing of the previous fractures with an overall improvement in the tubulation of the long bones. Conclusion: To our knowledge, this is the first report describing low ALP activity with phenotypic features of HPP in a neonate with severe perinatal OI due to a novel AD COL1A1 mutation. The low ALP could be due to osteoblasts dysfunction rather than ALPL gene causing enzyme deficiency & it highlights a potentially important role of osteoblasts in the pathogenesis of OI leading to reduced ALP activity and HPP phenotype. Interestingly, patients with lethal type II OI exhibit hypoplastic ribs and generalized hypomineralization; and, osteoblastic dysfunction has been suggested. It is tempting to speculate that low ALP activity may potentially have an additive effect on the severity and possibly lethality of certain most severe forms of OI contributing to potentially a new phenotype of this heterogeneous disorder. Long-term follow-up is needed to see if the patient will benefit from asfotase alfa treatment. In addition, further studies should be performed to truly understand the pathogenesis of the disease in this patient.

Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2.

Cardiac valvular Ehlers-Danlos syndrome (EDS) is a rare EDS subtype, caused by specific recessive variants in the gene encoding pro-α2-chain of type I collagen (COL1A2). Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate-severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features. Only five molecularly confirmed patients have been reported to date. Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2. Clinical data and literature review allowed to better define the clinical spectrum of cardiac valvular EDS which now emerges as a more recognizable EDS variant with progressive heart valve disease firstly affecting the mitral valve. Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis and hypoplasia of the interphalangeal creases. The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease.

Mutational spectrum of COL1A1 and COL1A2 in Egyptian patients with autosomal dominant osteogenesis imperfecta with clinical severity score and genotype/phenotype correlation

Medical Molecular Genetics, Division of HumanGenetics and Genome Research, Center of ScientificExcellence of Human Genetics, National ResearchCentre, Cairo, EgyptCorrespondence to Mohamed S. Abdel-Hamid, MSc,Department of Medical Molecular Genetics, Division ofHuman Genetics and Genome Research, Center ofScientific Excellence of Human Genetics, NationalResearch Centre, El-Buhouth St, Dokki, 12311 Cairo,EgyptTel: +20 1001667730; fax: +20 233 370 931;e-mail: mohamadnrc@hotmail.comReceived 10 October 2014Accepted 23 October 2014Middle East Journal of Medical Genetics2015, 4:7–12

Two mutations in IFITM5 causing distinct forms of osteogenesis imperfecta

The IFITM5 gene has recently been found to be mutated in patients with autosomal dominant osteogenesis imperfecta (OI) type V. This form of OI is characterized by distinctive clinical manifestations, including hyperplastic callus formation at the site of fractures, calcification of the interosseous membrane of the forearm, and dislocation of the head of the radius. Notably, in spite of the fact that a considerable number of patients with IFITM5 mutations have been identified, to date all of them have been shown to have the same heterozygous mutation (c.-14C>T). Herein, we describe one patient with a de novo c.119C>T heterozygous mutation in IFITM5, which predicts p.Ser40Leu, and another with the recurrent c.-14C>T transition that was also apparently de novo. While the patient with the p.Ser40Leu mutation had none of the typical signs of OI type V and was diagnosed with limb shortening at prenatal stages, the patient with the c.-14C>T mutation developed hyperplastic calluses and had calcification of the forearm interosseous membrane. This study challenges the lack of allelic and clinical heterogeneity in IFITM5 mutations.

Prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta associated with unaffected parents and paternal gonadal mosaicism

ObjectiveTo present the prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta (OI) associated with unaffected parents and paternal gonadal mosaicism. Materials and MethodsA 37-year-old woman was referred for genetic counseling at 18 weeks of gestation because of advanced maternal age and a family history of OI. The woman had a daughter who was affected with OI type III and carried an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene. The woman and her husband were non-consanguineous and healthy. Amniocentesis was performed at 18 weeks of gestation. ResultsCytogenetic analysis revealed a karyotype of 46,XX. Molecular analysis of the amniocytes revealed a recurrent mutation of c.4308_4309insA in exon 52 of the COL1A1 gene. Mutational analysis of the family revealed no mutation of the COL1A1 gene in the parental bloods. However, mosaicism for the COL1A1 mutation was found in the paternal sperms. Level II ultrasound examination showed a curved right tibia, a narrow chest with irregular ribs and mild frontal bossing in the fetus. The parents decided to terminate the pregnancy, and a female fetus was delivered at 23 weeks of gestation with curved long bones. ConclusionRecurrent autosomal dominant OI may occur in the offspring of unaffected parents with parental gonadal mosaicism. Genetic counseling of recurrent autosomal dominant OI should include a thorough mutational analysis of the family members, and mutational analysis of the sperm may detect paternal gonadal mosaicism for the mutation.

Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8

Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G>A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G>A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date.

Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research.

Nanoscale morphology of Type I collagen is altered in the Brtl mouse model of Osteogenesis Imperfecta

Bone has a complex hierarchical structure that has evolved to serve structural and metabolic roles in the body. Due to the complexity of bone structure and the number of diseases which affect the ultrastructural constituents of bone, it is important to develop quantitative methods to assess bone nanoscale properties. Autosomal dominant Osteogenesis Imperfecta results predominantly from glycine substitutions (80%) and splice site mutations (20%) in the genes encoding the α1 or α2 chains of Type I collagen. Genotype-phenotype correlations using over 830 collagen mutations have revealed that lethal mutations are located in regions crucial for collagen-ligand binding in the matrix. However, few of these correlations have been extended to collagen structure in bone. Here, an atomic force microscopy-based approach was used to image and quantitatively analyze the D-periodic spacing of Type I collagen fibrils in femora from heterozygous (Brtl/+) mice (α1(I)G349C), compared to wild type (WT) littermates. This disease system has a well-defined change in the col1α1 allele, leading to a well characterized alteration in collagen protein structure, which are directly related to altered Type I collagen nanoscale morphology, as measured by the D-periodic spacing. In Brtl/+ bone, the D-periodic spacing shows significantly greater variability on average and along the length of the bone compared to WT, although the average spacing was unchanged. Brtl/+ bone also had a significant difference in the population distribution of collagen D-period spacings. These changes may be due to the mutant collagen structure, or to the heterogeneity of collagen monomers in the Brtl/+ matrix. These observations at the nanoscale level provide insight into the structural basis for changes present in bone composition, geometry and mechanical integrity in Brtl/+ bones. Further studies are necessary to link these morphological observations to nanoscale mechanical integrity.

Lack of Cyclophilin B in Osteogenesis Imperfecta with Normal Collagen Folding

Osteogenesis imperfecta is a heritable disorder that causes bone fragility. Mutations in type I collagen result in autosomal dominant osteogenesis imperfecta, whereas mutations in either of two components of the collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-hydroxylase 1 [P3H1]) cause autosomal recessive osteogenesis imperfecta with rhizomelia (shortening of proximal segments of upper and lower limbs) and delayed collagen folding. We identified two siblings who had recessive osteogenesis imperfecta without rhizomelia. They had a homozygous start-codon mutation in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB), the third component of the complex. The proband's collagen had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis-trans isomerase that catalyzes the rate-limiting step in collagen folding, as is currently thought.

Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation

Background:Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin...

CRTAPandLEPRE1mutations in recessive osteogenesis imperfecta

Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen alpha1(I) and type II collagen alpha1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, "popcorn" epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.

Hearing loss (in nonoperated ears) in relation to age in osteogenesis imperfecta type I.

Hearing loss was studied in relation to age in nonoperated ears in a group of 142 subjects with autosomal dominant osteogenesis imperfecta type I, which was compared to that in a random subsample of 70 subjects. In the n = 142 group, particularly below the age of 30 years, considerable selection (ie, for ear surgery) had occurred on hearing loss. The hearing threshold increased gradually with age. A hearing loss of greater than 30 dB (Fletcher index) was observed for 51% of the subjects older than 20 years and younger than 60 years. The median hearing loss progressed from the 10th to the 45th years of life with an average annual threshold increase (ATI) of 1 dB/y (0.5 to 4 kHz) up to 1.7 dB/y (8 kHz). Sensorineural loss accounted for 0.6 dB/y ATI at 0.5 to 4 kHz and 1.3 dB/y ATI at 8 kHz; conductive loss accounted for 0.4 dB/y ATI at all frequencies.

Variable clinical expression in a family with OI type IV due to deletion of three base pairs in COL1A1.

We have studied a family with autosomal dominant osteogenesis imperfecta (OI) type IV. Electrophoresis of collagen produced by cultured fibroblasts revealed a slower migrating population of collagen I. Cyanogen bromide peptide mapping localised the structural defect to the area of the alpha 1(1)CB3 peptide. Subsequent sequencing revealed a deletion of nucleotides 1964-1966 in exon 27 of COL1A1. By means of restriction enzyme analysis, the deletion could be detected in all affected family members. This in-frame deletion resulted in the removal of alanine-438 and Glu437Asp substitution in the pro alpha 1(I) collagen chain. Clinical variation was considerable among affected family members. The most consistent clinical features were reduced height and extraosseous manifestations of OI.

Prenatal prediction of osteogenesis imperfecta (OI type IV): exclusion of inheritance using a collagen gene probe.

Autosomal dominant osteogenesis imperfecta is caused by mutations in the COL1A2 and COL1A1 genes of type I collagen. In a family with OI type IV genetically linked to the COL1A2 gene, we attempted prenatal diagnosis in a pregnancy at risk by genotyping the DNA of the fetus for a COL1A2 gene associated RFLP. Our results showed that the fetus inherited the normal COL1A2 allele from her affected parent. Linkage analysis can thus be used in the prenatal diagnosis of dominantly inherited osteogenesis imperfecta.

DOMINANTLY INHERITED OSTEOGENESIS IMPERFECTA (OI TYPES I AND IV) IS GENETICALLY LINKED TO THE COLIAI AND CJL1A2 GENES OF TYPE I COLLAGEN

Osteogenesis imperfecta (OI) is a genetically heterogeneous group of connective tissue disorders. Mutations in Type I collagen have been shown in a number of OI variants. Using restriction fragment length polymorphisms (RFLPs) associated with the two structural genes of Type I collagen we studied the segregation of these markers in families with autosomal dominant OI. The RFLPs have been previously reported (Tsipouras et al, Am.J. Hum. Genet. 1984: 36:1172-9, Sykes et al, Lancet 1986:2:69-72). In four families with OI type IV we observed concordant segregation to the COL1A2 RFLPs and discordant to the COL1A1. In one family with OI type I we observed concordance to the CUL1A1 and discordance to the COL1A2. Finally in one family with OI type I we observed discordance to both the COL1A1 and COL1A2. Our results suggest that: a) autosomal dominant OI is genetically heterogeneous and b) a locus other than the COL1A1 and COL1A2 may be involved in the etiology of OI.