BackgroundMutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family.MethodsTwo children initially diagnosed with idiopathic short stature (ISS) and a third mildly short child from a large Chinese family presented with poor GH response. Genetic etiology was identified by whole exome sequencing and confirmed via Sanger sequencing. Adult heights were analyzed, and the responses to GH treatment of the proband and two affected relatives are summarized and compared to other cases reported in the literature.ResultsA novel ACAN gene variant c.7465 T > C (p. Gln2364Pro), predicted to be disease causing, was discovered in the children, without evident syndromic short stature; mild bone abnormity was present in these children, including cervical-vertebral clefts and apophyses in the upper and lower thoracic vertebrae. Among the variant carriers, the average adult male and female heights were reduced by − 5.2 and − 3.9 standard deviation scores (SDS), respectively. After GH treatment of the three children, first-year heights increased from 0.23 to 0.33 SDS (cases in the literature: − 0.5 to 0.8 SDS), and the average yearly height improvement was 0.0 to 0.26 SDS (cases in the literature: − 0.5 to 0.9 SDS).ConclusionsWe report a novel pathogenic ACAN variant in a large Chinese family which can cause severe adult nonsyndromic short stature without evident family history of bone disease. The evaluated cases and the reports from the literature reveal a general trend of gradually diminishing yearly height growth (measured in SDS) over the course of GH treatment in variant-carrying children, highlighting the need to develop novel management regimens.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0591-z) contains supplementary material, which is available to authorized users.

Congenital hyperinsulinism (CHI) has been mostly associated with mutations in seven major genes. We retrospectively reviewed a cohort of 32 patients with CHI. Extensive mutational analysis (ABCC8,KCNJ11,GCK,GLUD1,HADH,HNF4A, and UCP2) was performed on Ion torrent platform, which could analyze hundreds of genes simultaneously with ultrahigh‐multiplex PCR using up to 6144 primer pairs in a single primer pool and address time‐sensitive samples with single‐day assays, from samples to annotated variants, to identify the genetic etiology of this disease. Thirty‐seven sequence changes were identified, including in ABCC8/KCNJ11 (n = 25, 65.7%), GCK (n = 2), HNF4A (n = 3), GLUD1 (n = 2), HADH (n = 4), and UCP2 (n = 1); these mutations included 14 disease‐causing mutations, eight rare SNPs, 14 common SNPs, and one novel mutation. Mutations were identified in 21 of 32 patients (65.6%). Among the patients with an identified mutation, 14 had mutations in ABCC8, one of which was combined with a GLUD1 mutation. Four patients had mutations in KCNJ11, 1 had a GCK mutation, 1 had a mutation in HADH, and two had a mutation in HNF4A. Among the 32 patients, the age at the onset of hyperinsulinemia ranged from the neonatal period to 1 year of age; five patients underwent a pancreatectomy due to intractable hyperinsulinemia. This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families.

Small interfering RNA (siRNA) functions through pairing with specific mRNA sequences and results in the mRNA’s degradation. It is a potential therapeutic approach for many diseases caused by altered gene expression. The delivery of siRNA is still a major problem due to its rapid degradation in the circulation. Various strategies have been proposed to help with the cellular uptake of siRNA and short or small hairpin RNA (shRNA). Here, we reviewed recently published data regarding local applications of siRNA. Compared with systemic delivery methods, local delivery of siRNA/shRNA has many advantages, such as targeting the specific tissues or organs, mimicking a gene knockout effect, or developing certain diseases models. The eye, brain, and tumor tissues are ‘hot’ target tissues/organs for local siRNA delivery. The siRNA can be delivered locally, in naked form, with chemical modifications, or in formulations with viral or non-viral vectors, such as liposomes and nanoparticles. This review provides a comprehensive overview of RNAi local administration and potential future applications in clinical treatment. [BMB Reports 2015; 48(3): 147-152]

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18 F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18 F DOPA-PET CT scanning–based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation. Conclusion : Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18 F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients . What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations . • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients .

CLCN7 gene encodes the voltage gated chloride channel 7 (ClC-7) in humans. The mutations in CLCN7 have been associated with osteopetrosis in connection to the abnormal osteoclasts functions. Previously, we found that some osteopetrosis patients with CLCN7 mutations suffered from impacted teeth and root dysplasia. Here we set up two in vivo models under a normal or an osteoclast-poor environment to investigate how ClC-7 affects tooth development and tooth eruption. Firstly, chitosan-Clcn7-siRNA nanoparticles were injected around the first maxillary molar germ of newborn mice and caused the delay of tooth eruption and deformed tooth with root dysplasia. Secondly, E13.5 molar germs infected with Clcn7 shRNA lentivirus were transplanted under the kidney capsule and presented the abnormal changes in dentin structure, periodontal tissue and cementum. All these teeth changes have been reported in the patients with CLCN7 mutation. In vitro studies of ameloblasts, odontoblasts and dental follicle cells (DFCs) were conducted to explore the involved mechanism. We found that Clcn7 deficiency affect the differentiation of these cells, as well as the interaction between DFCs and osteoclasts through RANKL/OPG pathway. We conclude that ClC-7 may affect tooth development by directly targeting tooth cells, and regulate tooth eruption through DFC mediated osteoclast pathway.