These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.

We made a genetic diagnosis in 61.8% of families and identified 33 mutations. SPAST mutations are the most common in Chinese AD-HSP followed by ATL1. Our findings broaden the genetic spectrum and improve the diagnosis of HSP.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.

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microRNAs (miRNAs) belong to a class of non-coding RNAs that regulate post-transcriptional gene expression during development and disease. Growing evidence indicates abundant miRNA expression changes and their important role in cardiac hypertrophy and failure. However, the role of miRNAs in fetal cardiac remodeling is little known. Here, we investigated the altered expression of fifteen miRNAs in rat fetal cardiac remodeling compared with adult cardiac remodeling. Among fifteen tested miRNAs, eleven and five miRNAs (miR-199a-5p, miR-214-3p, miR-155-3p, miR-155-5p and miR-499-5p) are significantly differentially expressed in fetal and adult cardiac remodeling, respectively. After comparison of miRNA expression in fetal and adult cardiac remodeling, we find that miRNA expression returns to the fetal level in adult cardiac failure and is activated in advance of the adult level in fetal failure. The current study highlights the contrary expression pattern between fetal and adult cardiac remodeling and that supports a novel potential therapeutic approach to treating heart failure.

Objective To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. Methods Whole‐exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. Results The clinical features of the patients showed late‐onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co‐segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense‐mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. Interpretation Variants in the MME gene were associated with not only a Charcot‐Marie‐Tooth neuropathy phenotype but also with an autosomal‐recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

Hereditary spastic paraplegia 73 (SPG73) was currently identified in only one family with variant in the neuronal isoform of carnitine palmitoyl‐transferase 1C (CPT1C) gene. We described a new family, in which affected individuals exhibited pure hereditary spastic paraplegia with benign clinical course. Exome sequencing revealed a novel nonsense variant in the CPT1C gene. The level of CPT1C mutant transcript significantly decreased compared to that of wild‐type transcript, and can be recovered after cycloheximide administration, which indicated that nonsense‐mediated mRNA decay was a mechanism that might be responsible for the phenotype. Our findings expanded the clinical and genetic spectrum of SPG73.

BackgroundAutosomal recessive cerebellar ataxias (ARCA) are a group of neurodegenerative disorders characterized by early onset of gait impairment, disturbed limb coordination, dysarthria, and eye movement abnormalities, most likely due to the degeneration of cerebellum, brainstem, and spinal cord. Despite of the rarity, ARCA are both clinically and genetically heterogeneous. To date, more than 30 culprit genes have been identified in ARCA. Unraveling the specific causative mutation in cases with ARCA remains challenging so far.MethodsThree ARCA pedigrees of Chinese ancestry were recruited. Clinical features were evaluated and peripheral blood was collected after obtaining the written inform. Laboratory examinations, brain MRI, and EMG were performed for all the affected individuals. Genomic DNA was extracted, followed by the screening of GAA repeat expansion in FXN gene to exclude Friedreich’s ataxia. Targeted next-generation sequencing combining Sanger sequencing was performed in each proband of these families.ResultsCompound heterozygous mutations, c.3190G > T (p.E1064X) and c.4883C > G (p.S1628X) of senataxin (SETX) gene were identified in one family with two affected cases. Both of the patients presented with early onset of unsteady walk, dysarthria, and diplopia. EMG test revealed decreased conduction velocity and evoked potential of both motor and sensory nerve. Moreover, elevated serum alpha-fetoprotein (AFP) and apparent cerebellar atrophy were observed. These features were typical features of ataxia with oculomotor apraxia type 2 (AOA2) and in line with the genetic results. However, no specific mutation was identified in the other two pedigrees.ConclusionsWe identified novel compound heterozygous mutations of SETX in Chinese AOA2 pedigree, which broaden the mutation spectrum of SETX. To our knowledge, this is the first report concerning Chinese AOA2 cases with SETX mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0696-y) contains supplementary material, which is available to authorized users.