Abstract
Summary
We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression.
Introduction
Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family.
Methods
We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated.
Results
The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient.
Conclusion
We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.
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Introduction
Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density (BMD), recurrent fractures, and progressive bone deformity [1]. Extra-skeletal features include blue sclera, hearing loss, dentinogenesis imperfecta, and joint hyperlaxity. As a collagen-related disorder, about 85–90% patients with OI are caused by mutations in genes encoding type I collagen, such as COL1A1 or COL1A2, with an autosomal dominant pattern of inheritance [2]. In addition, OI can be induced by mutations in genes, which regulate the post-translational modification (CRTAP, P3H1, PPIB, TMEM38B), secretion (SERPINH1, FKBP10), processing (PLOD2, BMP1) of type I collagen, as well as regulate osteoblast differentiation (WNT1, SP7) or bone mineralization (IFITM5, SERPINF1) [3,4,5,6,7,8].
In 2010, mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1, MIM 600943) was firstly reported to cause OI type X in human. SERPINH1 is located at 11q13.5 and encodes heat shock protein 47 (HSP47), which is a 418-amino-acid protein and belongs to the serpin superfamily [9,10,11]. HSP47 can prevent local unfolding and aggregate formation of procollagen and regulate the activity of lysyl hydroxylase 2 (LH2) by forming an endoplasmic ergatoplasm (ER) complex with FK506 binding protein (FKBP65) and immunoglobulin heavy-chain-binding protein (BiP) [12]. Inactivation mutations in SERPINH1 will cause incorrect aggregation and delayed secretion of type I procollagen molecules, which finally result in increased bone fragility and recurrent fractures [13].
To our knowledge, OI type X is extremely rare, and only five patients all over the world have been reported to carry four kinds of mutations in SERPINH1, which lead to autosomal recessive OI type X. Till now, no information about mutations in SERPINH1 is available in Chinese OI patients [13,14,15,16]. Moreover, bisphosphonates (BPs) are widely used to treat bone fragility of OI patients, which are demonstrated to be effective in increasing BMD and decreasing bone fracture incidence. Only one patient with SERPINH1 mutation was reported to receive pamidronate treatment; however, BMD was not increased after 2 years of BP treatment [14].
In the present study, we aim to investigate the phenotype, the pathogenic mutation, and the effects of BP treatment on bones of a Chinese patient with extremely rare OI type X.
Materials and methods
Subjects
A 5-year-old boy was recruited from a non-consanguineous Chinese family of Han origin by department of endocrinology of Peking Union Medical College Hospital (PUMCH) in 2008. He was clinically diagnosed with OI because of recurrent bone fractures, and he had no family history of bone fractures or bone deformities.
The study protocol was approved by the Scientific Research Ethics Committee of PUMCH, and the parents of the patient signed informed consent before they participated in this study.
Phenotype evaluation
The proband received detailed evaluation, including medical history, physical examination, biochemical index, and X-ray films. Bone fracture history and bone X-ray films were assessed to confirm the fracture number and sites. According to the standardized growth charts of Chinese children, age- and sex-adjusted Z score of height and weight were calculated. Fasting blood samples were collected for the biochemical analysis. The serum levels of calcium (Ca), phosphate (P), alkaline phosphatase (ALP), and creatinine (Cr) were measured by an automatic biochemical analyzer. Serum level of β-cross-linked C-telopeptide of type I collagen (β-CTX) was measured utilizing the automated Roche electrochemiluminescence system (Roche Diagnostics, Switzerland) at the central laboratory of PUMCH.
Radiographic assessments
BMD at lumbar spine 2–4 (LS) and femoral neck (FN) was measured using dual-energy X-ray absorptiometry (DXA, GE Lunar, USA) with appropriate pediatric software. Then, BMD Z-score was calculated according to reference data of BMD of Asian children [17]. X-ray films of the skull, thoracolumbar vertebrae, pelvis, and femurs were also examined.
Bisphosphonate treatment
The patient received oral alendronate (Fosamax, Merck Sharp & Dohme) 70 mg per week for 3 years and then received intravenous infusion of zoledronic acid (Aclasta, Novartis Pharma Stein AG) 5 mg annually for 4 years, with an intermittent discontinuation of 2 years because of fractures. During treatment, changes of BMD, serum levels of bone turnover markers (ALP and β-CTX), and fracture incidences were evaluated annually. Treatment safety was also evaluated including adverse effects of BPs, as well as liver and renal functions.
Molecular genetic analysis
Peripheral blood samples were obtained from the proband, his parents, and 100 unaffected healthy individuals. Genomic DNA was extracted from peripheral leukocytes under the standard protocols using the DNA Extraction Kit (QIAamp DNA, Qiagen, Frandfurt, Germany).
The DNA sample of the proband was sequenced by a targeted next-generation sequencing (NGS) panel (Illumina HiSeq2000 platform, Illumina, Inc., San Diego, CA, USA). The panel covered more than 700 genes that were implicated with bone disorders, which included candidate genes of OI (COL1A1, COL1A2, BMP1, CREB3L1, CRTAP, FKBP10, IFITM5, LEPRE1, P4HB, PLOD2, PPIB, PLS3, SEC24D, SERPINF1, SERPINH1, SP7, SPARK, TMEM38B, and WNT1). Sequencing was performed to 98.95% coverage for a mean depth of 200× on target regions in each of the chromosomes. NGS data was analyzed according to the protocol that was described previously [18]. Variants including missense mutations, nonsense mutations, frame shift mutations, and splice site mutations were expected to be pathogenic. Missense mutations causing substitution of amino acids were predicted with Polyphen2 software (http://genetics.bwh.harvard.edu/pph2/). Splice site mutations were predicted utilizing NNSPLICE0.9 (http://www.fruitfly.org/) and Human Splicing Finder (http://www.umd.be/HSF3/HSF.html).
To confirm the corresponding mutation in SERPINH1 gene identified by NGS, we performed Sanger sequencing. Genomic DNA from the proband and his parents were used to amplify the region surrounding exon 2 and exon 5 of SERPINH1 by polymerase chain reaction (PCR). Primers for PCR were as follows: F 5′-AGAGCTGAGGGTGGTTGTTG-3′, R 5′-GCACGGAATGTCGTCCTAAC-3′ for exon 2; F 5′-TCAGGGTAGTATGGGGTGGA-3′, R 5′-GGGAGAGGTTGGGATAGAGC-3′ for exon 5, which were designed by web-based Primer 3 (http://bioinfo.ut.ee/primer3-0.4.0/). Following an initial denaturation at 95 °C for 3 min, reactions were taken for 35 cycles of 95 °C for 30 s, 59–60 °C for 30 s, and 72 °C for 30–60 s. PCR products were then sequenced by ABI 377 DNA automated sequencer (Applied Biosystems) using standard protocols. Sanger sequencing was also performed in the 100 unrelated, healthy individuals to confirm that the mutations were not polymorphisms. The involving fragments were compared with the NCBI reference sequence of SERPINH1 (NM_001235.3).
Three-dimensional modeling of HSP47 protein
We also investigated the protein change caused by mutations in the SERPINH1 gene. The three-dimensional (3D) structure of the HSP47-collagen complex (PDB ID: 4AU2) was downloaded from Protein Data Bank. Then, the 3D structure of HSP47 was obtained by extracting the chain A of the PDB file 4AU2. Subsequently, the Lue50Arg and Arg405His mutants of HSP47 were built by mutagenesis module of PyMoL 1.7.6 software (http://www.pymol.org/). Finally, the models were verified by the Ramachandran plot.
Results
Phenotype of the patient
The clinical characteristics of the patient are shown in Table 1. The proband was a 14-year-old boy, the only child of the family. He was born full-term with a birth weight of 3100 g and a length of 50 cm. At 3 years old, he experienced bilateral femoral fracture for the first time. Subsequently, eight times of fractures occurred at his bilateral femurs under minor trauma from 3 to 5 years old. Gradually, his femurs became bowed and the movement of lower limbs was restricted. He came to our clinic at 5 years old. Physical examination revealed short stature, low weight (95 cm and 15 kg, all lower than the 3rd percentile of normal children), and apparent bending femurs. He had no scoliosis, blue sclera, hearing loss, and dentinogenesis imperfecta. X-ray films indicated severe osteoporosis, occipital wormian bone, deformities of proximal femurs, and slender long bone with thin cortical bone (Fig. 1a).
Mutations in SERPINH1
For the proband, novel compound heterozygous mutations were identified in SERPINH1: c.149 T>G in exon 2 (p.Leu50Arg) and c.1214 G>A in exon 5 (p.Arg405His), both of which led to amino acid substitutions (Fig. 2). These two missense mutations were predicted to be damaging with scores of 0.999 and 1.000 (Polyphen2), respectively. His father was a heterozygous carrier of mutation c.1214 G>A and his mother carried mutation of c.149 T>G. The affected HSP47 sequence was highly conserved across different species (Fig. 3b). The two missense mutations in SERPINH1 were absent from the 100 healthy controls. Other gene mutations related to OI were not found in this patient.
The changes of amino acid of HSP47 in 3D structure induced by the mutations in SERPINH1of our patient are shown in Fig. 4.
Efficacy of BP treatment
At baseline, the patient’s serum concentrations of Ca, P, ALP were within normal ranges. Since there was no normal reference of β-CTX in Chinese children, it was difficult to judge the result of β-CTX. His BMD and Z-scores at LS and FN were extremely low (Table 1). He received 3-year regular treatment of oral alendronate from 5 to 8 years old. Then, the treatment became intermittent because of fractures. When he was 10 years old, he received annually intravenous infusion of zoledronic acid for 4 years. After a total of 7 years of BP treatment, his BMD Z-score significantly increased from − 5.34 to 0.93 at LS, from − 5.06 to − 0.19 at FN, respectively (Fig. 1b). Average fracture rates decreased from 1.60 to 0.22 per year and compressed vertebrae were reshaped (Fig. 1a). During the treatment of alendronate, he experienced two fractures at left femur under minor trauma at his 6 and 8 years old, and no fracture happened when he received zoledronic acid treatment. His body length increased from 95 cm (5 years old) to 143 cm (14 years old), but Z-score of height was still low, from − 3.05 to − 3.18. The tolerance of the patients to alendronate and zoledronic acid was quite well and no obvious adverse events were found during the treatment.
Discussion
In the present study, we reported novel compound heterozygous mutations in SERPINH1 for the first time in Chinese OI patients, which led to the extremely rare OI type X. The boy suffered from early-onset recurrent fractures, bilateral femur deformities, and short stature, without typical extra-skeletal manifestations. We identified novel compound heterozygous mutations in SERPINH1 (c.149 T>G in exon 2 and c.1214G>A in exon 5) in this proband, and his parents were proved to be the heterozygous carriers for these mutations. BPs were effective in reducing fracture rate, increasing BMD and reshaping the compressed vertebrae in the proband with SERPINH1 mutations.
The exact mechanism of mutations in SERPINH1 causing OI has not been completely elucidated. HSP47, encoded by SERPINH1, is an ER (endoplasmic reticulum)-resident molecular chaperone which contributes to proper assembly of the collagen triple helix [19, 20]. HSP47 would effectively prevent local unfolding and aggregation of the procollagen by specifically recognizing its Gly-Xaa-Arg repeats [21, 22]. Moreover, HSP47 can bind the procollagen in the ER, and then dissociate with it in the Golgi compartment in a PH-dependent manner, making sure the correct transportation of type I procollagen [23]. In SERPINH1−/− mice, collagen synthesis was defective and the mice died at around 11 days after birth [24]. In a dachshunds model, loss-of-function mutations in SERPINH1 of OI could cause over modification and increased cross-linking of type I collagen [25, 26]. Therefore, SERPINH1 mutations could alter post-translational modification of collagen due to aggregation and delayed secretion of procollagen molecules. Moreover, HSP47 could regulate the activity of lysyl hydroxylase 2 (LH2) by forming an endoplasmic ergatoplasm (ER) complex with FK506 binding protein (FKBP65) and immunoglobulin heavy-chain-binding protein (BiP) [12], through which SERPINH1 mutations would lead to abnormal synthesis of type I collagen.
As far as we know, only six mutations in SERPINH1 have been reported in OI patients including our study (http://lovd.nl/serpinh1). The mutations including 4 missense mutations (c.233T>C in exon 2, c.710T>C in exon 3, c.149 T>G in exon 2, and c.1214G>A in exon 5) and 2 deletion mutation (c.338_357del22 in exon 2 and c.314_325del12 in exon 2), which are shown in Fig. 3a. In this study, we identified two heterozygous mutations in SERPINH1 gene in our patient, both of which were missense mutations (c.149 T>G and c.1214G>A). The c.149 T>G mutation caused Leu50Arg and the c.1214G>A led to Arg405His, respectively. Since Leu50 and Arg405 were highly conserved across different species, we speculated that these changes of the amino acids could impair the function of HSP47.
HSP47 consisted of nine α-helixes and three β-sheets (A, B, C), with a signal sequence at the amino-terminus, two amino-glycosylation sites, and an ER-retention signal (Arg-Asp-Glu-Leu, RDEL) at the carboxy-terminus. Arg222, Leu381, Tyr383, Asp385 on β-sheet C were suspected to be the key residues of HSP47 binding to collagen peptide [21]. Serine domain was the major functional domain of HSP47, which was responsible for its chaperone function in the folding of fibrillar procollagen molecules. The Leu50Arg affected one of α helix, and Arg405His influenced β sheet, both of which could interfere with physiological function and activity of serine domain. Therefore, these mutations would significantly affect the functions of HSP47, which would lead to OI through impairing the folding of procollagen molecules.
Up to now, only six patients with SERPINH1 mutations were reported, including our patient [13,14,15,16]. The phenotype of patients was obviously heterogeneous, which could vary from moderate to lethal (Table 2). Patient 2 suffered from multiple fractures in the ribs and severe deformities of bone, and finally died from respiratory distress at 3.5 years old. Patient 5 presented with perinatally lethal OI, who died at 8 days after birth. Similar with patients 3, 4, and 6, our patient (patient 1) presented with relatively moderate phenotype, with multiple fractures, obvious femoral deformity, and short stature. Extra-skeletal features, like blue sclera, hearing loss, and dentinogenesis imperfecta, were not found in patients 1, 3, and 4. However, it was difficult to establish genotype-phenotype correlation in OI patients with SERPINH1 mutations, because the sample size was fairly small.
Bisphosphonates (BPs) were demonstrated effective to increase BMD, decrease fracture incidence in children with OI [27, 28]. Long-term treatment of BPs was indicated to be safe and effective in small size of OI patients [29, 30]. In a prospective study, 91 children with OI received 3years of treatment with 70 mg alendronate weekly. During the treatment, the mean annual fracture incidence decreased from 1.2 to 0.2, with the BMD Z-score at LS increasing from − 3.0 to 0.1, and there were no severe adverse events that happened during the treatment [30]. In OI patients with SERPINH1 mutations, only two patients received BP therapy. Early at the age of 1 month, a patient was administrated with intravenous pamidronate acid every 2–4 months. However, his BMD at lumbar spine decreased from 0.246 to 0.210 g/cm2 from 1 to 2 years old [14]. In our patient, 7 years of BP treatment was demonstrated to be effective in reducing fracture rates, increasing BMD at lumbar spine and proximal hip, with good tolerance. Additionally, reshape of compressed vertebrae was observed in our patient after the treatment of intravenous infusion of zoledronic acid (Fig. 1a), which was in accord with Palomo’s research [31]. In Palomo’s research, 37 children with OI were included, who received BP treatment before 5 years old. After more than 10-year follow-up, the rate of vertebrae compression decreased from 35% at baseline to 6% at the last evaluation [31]. However, the efficacy of BP treatment in patients with SERPINH1 mutations still needed to be investigated in a large sample of patients.
In summary, we identified two missense mutations (c.149 T>G, p. Leu50Arg and c.1214 G>A, p. Arg405His) in SERPINH1, which resulted in extremely rare autosomal recessive OI type X. The patient presented with moderate phenotype of OI, including extremely low BMD, recurrent fracture, femoral deformities, and growth retardation. Long-term treatment of BPs was effective in increasing BMD, reducing fracture incidence, and reshaping vertebrae compression. Our findings of the novel mutations in SERPINH1 would enrich the genetic spectrum of OI type X and emphasize the role of HSP47 in the pathogenesis of OI.
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Acknowledgements
This study was supported by National Natural Science Foundation of China (No. 81570802) and CAMS Initiative for Innovative Medicine (2016-I2M-3-003). We sincerely thank the patient with SERPINH1 mutation and his parents for the participation in this research and thank all unaffected, unrelated individuals for providing control DNA samples.
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The study protocol was approved by the Scientific Research Ethics Committee of PUMCH, and the parents of the patient signed informed consent before they participated in this study.
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Song, Y., Zhao, D., Xu, X. et al. Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X. Osteoporos Int 29, 1389–1396 (2018). https://doi.org/10.1007/s00198-018-4448-2
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DOI: https://doi.org/10.1007/s00198-018-4448-2