Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy.

BACKGROUND: Mutations in the tropomyosin receptor kinase fused (TFG) gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and autosomal dominant type of Charcot-Marie-Tooth disease type 2. METHODS: Whole genome sequencing and whole-exome sequencing were used, followed by Sanger sequencing for validation. Haplotype analysis was performed to confirm the inheritance mode of the novel TFG mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported TFG mutation was studied. Clinical data and muscle pathology comparisons were drawn between patients with HSP and patients with HMSN-P. Furthermore, functional studies using skin fibroblasts derived from patients with HSP and patients with HMSN-P were conducted to investigate the pathomechanisms of TFG mutations. RESULTS: A novel heterozygous TFG variant (NM_006070.6: c.125G>A (p.R42Q)) was identified and caused pure HSP. We further confirmed that the well-documented recessively inherited spastic paraplegia, caused by homozygous TFG mutations, exists in a dominantly inherited form. Although the clinical features and muscle pathology between patients with HSP and patients with HMSN-P were distinct, skin fibroblasts derived from both patient groups exhibited reduced levels of autophagy-related proteins and the presence of TFG-positive puncta. CONCLUSIONS: Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by TFG mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.

Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common neurodegenerative disorder of the peripheral nervous system. More than 50 genes/loci were found associated with the disease. We found a family with autosomal-dominant CMT2. OBJECTIVE: To reveal the pathogenic gene of the family and further investigate the function of the variant. METHODS: DNA underwent whole-genome linkage analysis for all family members and whole-exome sequencing for 2 affected members. Neurofilament light polypeptide and wild-type or mutant neurofilament heavy polypeptide (NEFH) were co-transfected into SW13 (vim-) cells. The nefh-knockdown zebrafish model was produced by using morpholino antisense oligonucleotides. RESULTS: We identified a novel insertion variant (c.3057insG) in NEFH in the family. The variant led to the loss of a stop codon and an extended 41 amino acids in the protein. Immunofluorescence results revealed that mutant NEFH disrupted the neurofilament network and induced aggregation of NEFH protein. Knockdown of nefh in zebrafish caused a slightly or severely curled tail. The motor ability of nefh-knockdown embryos was impaired or even absent, and the embryos showed developmental defects of axons in motor neurons. The abnormal phenotype and axonal developmental defects could be rescued by injection of human wild-type but not human mutant NEFH mRNA. CONCLUSIONS: We identified a novel stop loss variant in NEFH that is likely pathogenic for CMT2, and the results provide further evidence for the role of an aberrant assembly of neurofilament in CMT.

Low-dose bisphenol A impairs the function of mouse decidual stromal cells by activating LUMAN-mediated unfolded protein response.

The nonsteroidal estrogenic compound bisphenol A (BPA) is widely present in several industrial and medical products including plastic food containers and sealants in dentistry. There are growing concerns on the toxic effects of this compounds since BPA is known to have reproductive toxicity. This study evaluated the effects of low-dose BPA exposure on decidual stromal cells (DSCs) of mice. The results showed that although 10 nM of BPA have no significant effect on the cell viability, it alters the expression of decidualization-related genes including Prl8a2, Prl3c1, Ptgs2, and Mmp2. Moreover, we found that low-dose BPA exposure induces UPR response in DSCs. However, the expression of the three major UPR receptors (Perk, Ire 1, and Xbp1) did not change significantly. Interestingly, the expression of Luman, a novel receptor of UPR, was significantly upregulated in a dose-dependent manner. Lentivirus containing shLuman sequence was used to generate stable Luman silencing DSCs. It's showed that Luman knockdown could affect the expression of decidualization-related genes in decidual cells after BPA treatment. In summary, these results suggest that Luman plays a key role in low dose BPA-induced decidual toxicity of DSCs in mouse.

A novel deletion mutation in GJB1 causes X-linked Charcot-Marie-Tooth disease in a Han Chinese family.

X-linked Charcot-Marie-Tooth disease CMT (CMTX) is predominantly caused by mutations in the GJB1 gene that encode connexin32. We describe the clinical findings and the identification of a novel mutation in GJB1 in a large Han Chinese family with CMTX. Linkage to GJB1 was determined by genotyping five polymorphic markers flanking GJB1. Sequence alterations were determined by directly sequencing the coding region of the GJB1 gene. The affected members have variable clinical manifestations. Linkage analysis confirmed the cosegregation of the disease with the GJB1 locus. Sequencing of the GJB1 gene revealed a 1-basepair deletion (c.110delT) in the coding region. The frameshift begins at amino acid 37 and generates a premature stop codon at position 83. The shortened peptide is unlikely to be functional, as it lacks most of the functional domains. The CMTX in this family is caused by a novel loss of function mutation.

Aesthetic outcome of intralesional injection of lauromacrogol as a single-agent treatment for uncomplicated infantile hemangiomas: A long-term follow-up study.

Infantile hemangiomas (IH) are at risk of incomplete regression with remnant permanent sequelae, ranging from passive waiting for spontaneous regression to active systemic administration. The application of traditional therapy involving injection of a sclerosing agent is limited due to the difficulty in achieving cosmetic improvement. This study aimed to explore a new injection method that could not only promote tumor regression but also achieve cosmetic improvement. A total of 122 IH (from 109 children) injected intralesionally with lauromacrogol in the Plastic Surgery Department of Fujian Medical University Union Hospital between 1 January 2012 and 1 June 2019 were enrolled in this study. The mean follow-up time was 2.9 years. Of 122 lesions studied, 111 (91.0%) achieved complete regression, 10 (8.2%) achieved significant regression and one (0.8%) achieved moderate regression. In terms of aesthetic appearance, 70 (57.4%) IH had no sequelae and the A score was 5/5. Twenty-one (17.2%) IH had minimal hyperpigmentation, hypopigmentation or telangiectasia and the A score was 4/5. Thirty-one (25.4%) IH had left mild or relatively obvious sequelae and the A score was 1-3/5. None of the 122 IH involved had rebound growth after terminating the treatment. Hyper- or hypopigmentation gradually faded over time and part of the IH had already returned to normal appearance by the time of long-term follow up. The results indicated that this new type of injection therapy significantly promoted the regression of uncomplicated IH and helped achieve the expected cosmetic appearance.