A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree.

Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies. Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2. Genome-wide linkage analysis showed that the disease phenotype is closely linked to chromosomal region 10p13-14, which spans 5.41 Mb between D10S585 and D10S1477. DNA-sequencing analysis revealed a nonsense mutation, c.1455T>G (p.Tyr485(∗)), in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals, but not in other unaffected individuals in this family or in 250 unrelated normal persons. DHTKD1 mRNA expression levels in peripheral blood of affected persons were observed to be half of those in unaffected individuals. In vitro studies have shown that, compared to wild-type mRNA and DHTKD1, mutant mRNA and truncated DHTKD1 are significantly decreased by rapid mRNA decay in transfected cells. Inhibition of nonsense-mediated mRNA decay by UPF1 silencing effectively rescued the decreased levels of mutant mRNA and protein. More importantly, DHTKD1 silencing was found to lead to impaired energy production, evidenced by decreased ATP, total NAD(+) and NADH, and NADH levels. In conclusion, our data demonstrate that the heterozygous nonsense mutation in DHTKD1 is one of CMT2-causative genetic alterations, implicating an important role for DHTKD1 in mitochondrial energy production and neurological development.

[Correlation of IgG Subclass with Blood Cell Parameters in Patients with Autoimmune Hemolytic anemia].

OBJECTIVE: To investigate the correlation of IgG subclasses with blood cell parameters in the patients with autoimmune hemolytic anemia (AIHA). METHODS: Thirty-four patients with AIHA (except C3d types) of immune complex type (IgG+C3d) and single IgG type, including 26 cases of primary AIHA and 8 cases of secondary AIHA from December 2010 to August 2016 in our hospital were selected and enrolled in AIHA group; 30 healthy persons were selected and enrolled in healthy control group. The levels of IgG subclasses in blood plasma were detected by double antibody sandwich ELISA in healthy persons and AIHA patients, at the same time. The levels of IgG subclasses in of RBC diffuse fluid were detected as well. The relation of IgG subclass level with some parameters of blood cells was analyzed in the hight of partial parameters of blood cells in patients. The independent sample test was used for comparison of data in 2 groups, the Spearman method was used for correlation analyziz. RESULTS: The average value of IgG1-4 in AIHA group was higher than that in healthy control group, there was statisticad difference between 2 groups (IgG1: t=-4.88, P<0.01; IgG2: t=-3.06. P<0.01; IgG3: t=-5.39, P<0.01; IgG4: t=-3.16, P<0.01), but the comparison of various. IgG subclass ratio in 2 groups showed that in addition to IgG4 (t=1.73, P >0.01) the ratio pf IgG1, IgG2 and IgG3 all had the statistical differences (IgG1: t=4.03, P<0.01; IgG2: t=7.38, P<0.01; IgG3: t=3.03, P<0.01). The spearmen analysis of corrclation of IgG subclass in blood plasma of patients with partial parameters of blood cells showed that the IgG4 positivety correlated with Hb level, the RBC count and HCT (Hb: r=0.358, P<0.05; RBC: r=0.426, P<0.05; HCT: r=0.363, P<0.05); the IgG1 and IgG2 negatively correlated with WBC count (IgG1: r=0.437, P<0.05; IgG2: r=-0.487, P<0.01); the IgG2 negatively correlated with count (r=-0.436, P<0.05). The comparison of IgG subclass ratio in plasma and RBC diffuse fluid of patients showed that in addition to IgG2 (t=1.544, P＞0.05), the rest IgG1, 3 and 4 all had statistical differences (IgG1: t=6.528, P<0.01; IgG3: t=-9.488, P<0.05; IgG4: t=-9.434, P<0.05). CONCLUSIONS: The AIHA relates with IgG1 and IgG3, the detection of IgG subclasses may have a certain significance for studying the diagnosis, treatment and pothogenesis of AIHA.