Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non-syndromic X-linked intellectual disability family

Abstract X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score ≤ 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease.

Inhibition of GDP on mitochondrial respiratory oxygen consumption and its effect on the mitochondrial membrane potential of rat brain / 第三军医大学学报

Objective To investigate effect of guanosine diphosphate (GDP) on the mitochondrial respiratory oxygen consumption and the mitochondrial membrane potential (MMP) of rat brain and explore the relationship of the change of uncoupling proteins (UCPS) activity with the oxygen consumption and MMP. Methods The mitochondria of rat brain were isolated by centrifugation. Mitochondria oxidative respiratory consumption was measured by Clark electrode after the treatment of GDP at different concentrations so as to calculate mitochondrial state 3 respiration (ST3), mitochondrial state 4 respiration (ST4), respiratory control rate (RCR), and the rate of oxidative phosphorylation (OPR). MMP was detected by Rhodamine 123 method at the different concentrations of GDP. Results With the increase of GDP concentration form 0 to 1.0 mmol/L, the values of ST3, ST4 and OPR were reduced while RCR was elevated. But when the concentration increased to 1.4 mmol/L, the former 3 indexes begun to increase while the later declined. When the GDP concentration reached to 1 mmol/L, the inhibitory rate was only 35.1%, 51.3%, 14.2% to ST3, ST4 and OPR respectively, while RCR was increased to 133.2%. No matter the concentration was over 1 mmol/L or under 1 mmol/L, the ability of inhibition was attenuated. MMP reached to the highest point when GDP exerted the highest inhibitory rate on mitochondrial respiratory oxygen consumption. Conclusion GDP, an inhibitor of UCPS, can regulate the respiratory oxygen consumption and MMP of the isolated rat brain mitochondrial directly in a dose-effect fashion. The change of UCPS activity can affect the respiratory oxygen consumption and MMP.