Mutations in SPATA5 have recently been shown to result in a phenotype of microcephaly, intellectual disability, seizures, and hearing loss in childhood. Our aim in this report is to delineate the ...SPATA5 syndrome as a clinical entity, including the facial appearance, neurophysiological, and neuroimaging findings. Using whole‐exome sequencing and Sanger sequencing, we identified three children with SPATA5 mutations from two families. Two siblings carried compound heterozygous mutations, c.989_991del (p.Thr330del) and c.2130_2133del (p.Glu711Profs*21), and the third child had c.967T>A (p.Phe323Ile) and c.2146G>C (p.Ala716Pro) mutations. The three patients manifested microcephaly, psychomotor retardation, hypotonus or hypertonus, and bilateral hearing loss from early infancy. Common facies were a depressed nasal bridge/ridge, broad eyebrows, and retrognathia. Epileptic spasms or tonic seizures emerged at 6–12 months of age. Interictal electroencephalography showed multifocal spikes and bursts of asynchronous diffuse spike‐wave complexes. Augmented amplitudes of visually evoked potentials were detected in two patients. Magnetic resonance imaging revealed hypomyelination, thin corpus callosum, and progressive cerebral atrophy. Blood copper levels were also elevated or close to the upper normal levels in these children. Clinical delineation of the SPATA5‐related encephalopathy should improve diagnosis, facilitating further clinical and molecular investigation.
Absence of brainstem auditory evoked potentials and augmented visually evoked potentials, hypomyelination and progressive cerebral atrophy, as well as decreased choline and increased lactate peaks observed in STATA5‐related encephalopathy.
Competitive inhibitors of either α-galactosidase (α-Gal) or β-galactosidase (β-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally ...locked sp(2)-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal α- and β-Gal associated with Fabry disease and GM(1) gangliosidosis.
LAMB1 gene analysis should be considered for intellectually disabled patients with cerebellar cysts, white matter signal change, and cortical malformation. Muscular involvement is absent, in contrast ...to the α‐dystroglycanopathy types of congenital muscular dystrophies.
Context: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth.
Objective: We hypothesized ...that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR).
Patients: Twenty-four children with unexplained IUGR (birth weight < −1.5 sd) and short stature (<−2.0 sd) were screened for abnormalities of the IGF-IR gene.
Methods: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and β-subunit autophosphorylation.
Results: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 ± 26% of normal) and less mature β-subunit protein (63 ± 12%); 3) 125IIGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 ± 0.16 × 106 vs. 1.14 ± 0.12 × 106 sites per cell; P < 0.05); and 4) both IGF-I-stimulated 3Hthymidine incorporation and IGF-IR β-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05).
Conclusions: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.
Von Hippel-Lindau disease is an autosomal dominantly inherited and multisystic tumor syndrome caused by mutation in the VHL gene. These mutations were reported from various countries with a variety ...of races. Even in a country, the different genotypes and phenotypes were reported. Therefore we reviewed these correlation of genotypes and phenotypes using previously reported infinite cases and our experienced cases. Moreover, we tried establishing a classification including the information about genetic change and exhibiting tumors. Finally, We assessed whether it is possible to predict an occurence of de novo tumors and developping of VHL disease.
A series of conformationally locked C-glycosides based on the 3-aminopyrano3,2-bpyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael ...addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver β-glucosidase/β-galactosidase and specific inhibition of human β-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol.
The expression of voltage-dependent K(+) channels (K(v) ) 1.5 is regulated by members of the heat shock protein (Hsp) family. We examined whether the heat shock transcription factor 1 (HSF-1) and its ...inducer geranylgeranylacetone (GGA) could affect the expression of K(v) 1.5 channels and its anchoring protein, synapse associated protein 97 (SAP97).
Transfected mouse atrial cardiomyocytes (HL-1 cells) and COS7 cells were subjected to luciferase reporter gene assay and whole-cell patch clamp. Protein and mRNA extracts were subjected to Western blot and quantitative real-time polymerase chain reaction.
Heat shock of HL-1 cells induced expression of Hsp70, HSF-1, SAP97 and K(v) 1.5 proteins. These effects were reproduced by wild-type HSF-1. Both heat shock and expression of HSF-1, but not the R71G mutant, increased the SAP97 mRNA level. Small interfering RNA (siRNA) against SAP97 abolished HSF-1-induced increase of K(v) 1.5 and SAP97 proteins. A luciferase reporter gene assay revealed that the SAP97 promoter region (from -919 to -740) that contains heat shock elements (HSEs) was required for this induction. Suppression of SIRT1 function either by nicotinamide or siRNA decreased the level of SAP97 mRNA. SIRT1 activation by resveratrol had opposing effects. A treatment of the cells with GGA increased the level of SAP97 mRNA, K(v) 1.5 proteins and I(Kur) current, which could be modified with either resveratrol or nicotinamide.
HSF-1 induced transcription of SAP97 through SIRT1-dependent interaction with HSEs; the increase in SAP97 resulted in stabilization of K(v)1.5 channels. These effects were mimicked by GGA.
A single intravenous injection with 4 x 10(7) PFU of recombinant adenovirus encoding mouse beta-galactosidase cDNA to newborn mice provided widespread increases of beta-galactosidase activity, and ...attenuated the development of the disease including the brain at least for 60 days. The beta-galactosidase activity showed 2-4 times as high a normal activity in the liver and lung, and 50 times in the heart. In the brain, while the activity was only 10-20% of normal, the efficacy of the treatment was distinct. At the 30th day after the injection, significant attenuation of ganglioside GM1 accumulation in the cerebrum was shown in three out of seven mice. At the 60th day after the injection, the amount of ganglioside GM1 was above the normal range in all treated mice, which was speculated to be the result of reaccumulation. However, the values were still definitely lower in most of the treated mice than those in untreated mice. In the histopathological study, X-gal-positive cells, which showed the expression of exogenous beta-galactosidase gene, were observed in the brain. It is noteworthy that neonatal administration via blood vessels provided access to the central nervous system because of the incompletely formed blood-brain barrier.
Strategies for successful infection of host plants are highly diverse in fungal pathogens, which range from biotrophs to necrotrophs. As more microbial genomes have been sequenced, more fungal genes ...have been identified as being involved in pathogenesis, as exemplified by those for biosynthesis of toxic secondary metabolites such as host-specific toxins. Filamentous fungi produce a diverse array of secondary metabolites-small molecules that are not necessary for normal growth or development. The role of host-specific toxins in plant-fungus interaction as well as the biochemistry and molecular basis of toxin biosynthesis are discussed. The availability of fungal genomic sequences has revealed a remarkably large number of biosynthetic gene clusters for secondary metabolites, e.g., polyketides and nonribosomal peptides including cyclic peptides, extremely large classes of natural products of fungal origin. The origin and evolutionary processes for these gene clusters are largely unknown. Analysis of the arrangement and sequences of genes in the clusters should shed light on how the clusters and abilities to produce toxic secondary metabolites evolved.
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