Ou Wang

Suppressed bone turnover was associated with increased osteoporotic fracture risks in non-obese postmenopausal Chinese women with type 2 diabetes mellitus

SummaryWe found that type 2 diabetes mellitus (T2DM) was associated with increased fracture risks in non-obese postmenopausal Chinese women, and suppressed bone turnover might be the underlying mechanism. This is the first study evaluating and explaining the association of T2DM with osteoporotic fracture in Chinese population with such high homogeneity.IntroductionThe aim of this study was to investigate the association of T2DM with osteoporotic fracture in postmenopausal Chinese women.MethodsOne thousand four hundred ten postmenopausal women were included and stratified into non-obese population [body mass index (BMI)u2009<u200925xa0kg/m2] and obese population (BMIu2009≥u200925xa0kg/m2). Each type of population was classified into diabetes group, impaired fasting glucose (IFG) group, and normal glucose group. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum C-terminal telopeptide of type I collagen (β-CTX) and serum N-amino terminal prepeptide of type 1 procollagen (P1NP) were quantified. Vertebral fractures (VFs) and non-VFs were assessed by vertebral X-ray and questionnaire, respectively.ResultsComparing to normal glucose group, diabetes group and IFG group both had lower levels of P1NP and β-CTX, despite population types. Despite having non-decreased BMD, non-obese diabetic patients had higher risks of total fracture and VF than BMI-matched normal glucose subjects (both Pu2009<u20090.05). Non-obese population was further classified by a mean value of P1NP or β-CTX. Non-obese diabetic patients with low P1NP or high β-CTX had higher fracture risks (both Pu2009<u20090.05), comparing to non-obese normal glucose subjects with high P1NP or high β-CTX, respectively.ConclusionsType 2 diabetic patients had suppressed bone turnover, which might explain the increased fracture risks, independent of BMD. IFG patients might also have poor bone quality and need early prevention.

A Recurrent Mutation c.617G>A in the ACVR1 Gene Causes Fibrodysplasia Ossificans Progressiva in Two Chinese Patients

Fibrodysplasia ossificans progressiva (FOP; OMIM 135100) is a rare heritable disorder of connective tissue characterized by congenital malformations of the great toes and recurrent episodes of painful soft tissue swelling that lead to heterotopic ossifications. Recent studies have shown that the ACVR1 (activin A receptor, type I; OMIM 102576) gene, which encodes the BMP type I receptor protein, is responsible for this disease. We observed two Chinese patients who suffered from progressive pain and ankylosis of major joints with congenital bilateral hallus valgus malformation, neck stiffness, and several posttraumatic ossified lesions on the head and dorsum. Both patients were diagnosed as having FOP. This study aimed to investigate the ACVR1 gene mutation in Chinese FOP patients. Direct sequence analysis of genomic DNA and restriction enzyme digestion demonstrated the presence of a single heterozygous c.617G>A (p.R206H) mutation in the ACVR1 gene in both patients. This mutation is first reported in Chinese patients with FOP and it was de novo in both affected families.

A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures, and skull deformities. Mutation in the gene encoding cathepsin K (CTSK), which is a lysosomal cysteine protease, has been found to be responsible for this disease. Here we reported a consanguineous Chinese family with 1 affected individual demonstrating autosomal recessive pycnodysostosis with recurrent kidney stone, a new clinical manifestation which has not been reported in patients of pycnodysostosis before. To identify the pathogenic mutation, we evaluated the patient clinically, biochemically, and radiographically. To screen for mutations in the CTSK gene of the patient and his family members, all of its exons and exon–intron junctions were PCR amplified from genomic DNA and sequenced. Sequence analysis of the patient’s CTSK gene revealed homozygosity for a missense mutation (c.746T>C) in exon 6, which leads to amino change (p.Ile249Thr) in the mature CTSK protein. This mutation was firstly reported by Michela Donnarumma and his colleagues in 2007 in a Spanish family. Our study strengthens the role of this particular mutation in the pathogenesis of pycnodysostosis.

Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients

SummaryOsteopetrosis is a group of genetic bone disorders. Mutations in the chloride channel 7 gene (CLCN7) lead to chloride channel defect, which results in autosomal dominant osteopetrosis type II (ADO-II), autosomal recessive osteopetrosis (ARO), and intermediate autosomal recessive osteopetrosis (IARO). In the present study, we identified seven novel mutations of the CLCN7 gene and reported the first case of IARO with compound heterozygous mutation in Chinese population.IntroductionOsteopetrosis is a heritable bone disorder due to the deficiency of or function defect in osteoclasts. Mutations in the CLCN7 lead to chloride channel defects, which result in osteopetrosis with diverse severity ranging from asymptomatic or relatively mild symptoms in ADO-II to the very severe phenotype in ARO. Heterozygous mutations in CLCN7 are associated to ADO-II, while homozygous and compound heterozygous mutations in CLCN7 may result in ARO and IARO. To date, a total of 24 mutations in CLCN7 were identified in ADO-II, and only 3 mutations were identified in IARO. In the present study, we reported seven unrelated ADO-II patients and one IARO patient from Chinese population and elucidated the characteristics of CLCN7 gene mutations in these patients.MethodsAll 25 CLCN7 exons and exon-intron boundaries from genomic DNA were amplified and sequenced in eight affected individuals suffering from ADO-II/IARO. The clinical, biochemical, and radiographic analysis were evaluated to compare the differences between ADO-II and IARO both in genotype and phenotype.ResultsThe results showed that there were seven novel CLCN7 mutations identified in these ADO-II/IARO patients, including six heterozygous missense mutations (p.L224R, p.S290Y, p.R326G, p.G347R, p.S473N, and p.L564P) and a novel splice mutation (p.K691FS).ConclusionsThe compound heterozygous mutations (p.L224R and p.K691FS) were firstly observed in one IARO patient. The present study would enrich the database of CLCN7 mutations and improve our understanding of this heritable bone disorder.

Familial Early-Onset Paget’s Disease of Bone Associated with a Novel hnRNPA2B1 Mutation

Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion body myopathy (IBM), PDB, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.

A Common Mutation and a Novel Mutation in the HPGD Gene in Nine Patients with Primary Hypertrophic Osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease characterized by digital clubbing, periostosis, and pachydermia. The HPGD gene encoding 15-prostaglandin dehydrogenase and SLCO2A1 encoding one type of prostaglandin transporter were found to be responsible for PHO. Mutations of either gene would lead to increased level of prostaglandin E2 (PGE2), which might contribute to the constellation of the symptoms. The aim of the study was to analyze the HPGD gene and the clinical characteristics in nine patients with the diagnosis of PHO. Nine patients, (eight males and one female) including two siblings and seven sporadic cases, were enrolled in the study. Clinical features were summarized, and blood and urine samples were collected. Sanger method was used to sequence the HPGD gene to detect mutations. Urinary PGE2 and prostaglandin metabolite (PGE-M) levels for each patient were measured and compared to the healthy controls. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). The levels of PGE2 in urine were much higher than normal in all patients, along with lower PGE-M levels. In conclusion, nine PHO patients were characterized by typical clinical manifestations including digital clubbing, periostosis, and pachydermia. A common mutation and a novel mutation in HPGD gene were identified to be responsible for the disease, and c.310_311delCT mutation is likely to be a hot-spot mutation site for Asian PHO patients.

A novel large fragment deletion in PLS3 causes rare X-linked early-onset osteoporosis and response to zoledronic acid

SummaryWe identified a novel large fragment deletion from intron 9 to 3’UTR in PLS3 (E10-E16del) in one Chinese boy with X-linked early-onset osteoporosis and vertebral fractures, which expanded the pathogenic spectrum of X-linked early-onset osteoporosis. Treatment with zoledronic acid was beneficial for increasing BMD and reshaping the vertebral bodies of this patient.IntroductionX-linked early-onset osteoporosis is a rare disease, which is characterized by low bone mineral density (BMD), vertebral compression fractures (VCFs), and/or long bone fractures. We aimed to detect the phenotype and the underlying pathogenic mutation of X-linked early-onset osteoporosis in a boy from a nonconsanguineous Chinese family.MethodsWe investigated the pathogenic mutation of the patient with X-linked early-onset osteoporosis by targeted next-generation sequencing and confirmed it by Sanger sequencing. We also observed the effects of zoledronic acid on fracture frequency and BMD of the patient.ResultsLow BMD and multiple VCFs were the main phenotypes of X-linked early-onset osteoporosis. We identified a total of 12,229xa0bp deletion in PLS3, involving intron 9 to the 3’UTR (E10-E16 del). This large fragment deletion might be mediated by Alu repeats and microhomology of 26xa0bp at each breakpoint junction. Zoledronic acid treatment could significantly increase the Z-score of BMD and reshape the compressed vertebral bodies.ConclusionWe identified a large fragment deletion mutation in PLS3 for the first time and elucidated the possible mechanism of the deletion, which led to X-linked early-onset osteoporosis and multiple vertebral fractures. Our findings would enrich the etiology spectrum of this rare disease.

Two novel CAII mutations causing carbonic anhydrase II deficiency syndrome in two unrelated Chinese families

The carbonic anhydrase II (CAII) deficiency syndrome is a rare autosomal recessive osteopetrosis with renal tubular acidosis (RTA) and cerebral calcifications (MIM259730). CAII deficiency syndrome is caused by mutations in the gene CAII, which encodes the enzyme carbonic anhydrase II. CAII mutations are rarely reported in the Asian population. Here, we described two unrelated CAII deficiency families of Chinese Han origin with clinical and genetic analysis. Altogether, 106 subjects, including 2 probands, 4 unaffected family members from two non-consanguineous Chinese families, and 100 healthy controls were recruited. All seven exons and the exon-intron boundaries of the CAII gene were amplified and directly sequenced. Reverse transcription PCR (RT-PCR) was used to study the effect of splice site mutation. All clinical and biochemical parameters of the probands were collected. Two novel mutations of CAII gene were identified by mutational analysis: A nonsense mutation in exon 4 (c.T381C p.Y127X) in both families; a splice mutation at the splice donor site of intron 3 (c.350+2T>C, IVS3+2T>C) in one family. The splice-site mutation causes exon 3 skipping in patient’s mRNA resulting in an in-frame deletion and a novel premature stop codon. These mutations were predicted to result in a loss of function of CAII. This is the first report of CAII deficiency syndrome in Chinese population. Our findings extent the spectrum of CAII mutations observed in patients with CAII deficiency syndrome.

Primary hyperparathyroidism in Chinese children and adolescents: A single‐centre experience at Peking Union Medical College Hospital

Primary hyperparathyroidism (PHPT) in children is thought to be extremely rare. Our study aimed to summarize the clinical characteristics and the molecular genetics in patients with paediatric PHPT in China.

First Report of a Novel Missense CLDN19 Mutations Causing Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in a Chinese Family

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder caused by mutations in the CLDN16 or CLDN19 genes, encoding claudin-16 and claudin-19 in the thick ascending limb of Henle’s loop. In patients with claudin-19 mutations, severe ocular involvement (macular coloboma, pigmentary retinitis, nystagmus, or visual loss) has been described. In this report, we presented a 12-year-old girl with rickets, polyuria, and polydipsia. She was the daughter of consanguineous parents, and she had a history of recurred hypocalcemic and hypomagnesemic tetany. On physical examination, bilateral horizontal nystagmus and severe myopia were detected. Laboratory examination revealed hypomagnesemia, hypocalcemia, hypercalciuria, nephrocalcinosis, and renal stone. A clinical diagnosis of FHHNC caused possibly by claudin-19 mutation was decided with the ocular findings. DNA analysis revealed a novel homozygous missense mutation c.241C>T in the CLDN19 gene. In conclusion, in a patient with hypomagnesemia, hypercalciuria, nephrocalcinosis, and ocular findings, a diagnosis of FHHNC caused by claudin-19 mutation should be considered. This is the first study of FHHNC in Chinese population. Our findings of the novel mutation c.241C>T in exon 2 add to the list of more than 16 mutations of CLDN19 gene reported.