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Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17[beta]) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by [NAD.sup.+] the Hill coefficient of the mutant enzyme is [approximately equal to] 1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the [gamma]-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17[beta]) dehydrogenase 10 deficiency. developmental disabilities | HSD10 deficiency | hydroxyacyl-CoA dehydrogenase

The fragile X mental retardation protein (FMRP), the functional absence of which causes fragile X syndrome, is an RNA-binding protein that has been implicated in the regulation of local protein synthesis at the synapse. The mechanism of FMRP's interaction with its target mRNAs, however, has remained controversial. In one model, it has been proposed that BC1 RNA, a small nonprotein-coding RNA that localizes to synaptodendritic domains, operates as a requisite adaptor by specifically binding to both FMRP and, via direct base-pairing, to FMRP target mRNAs. Other models posit that FMRP interacts with its target mRNAs directly, i.e., in a BC1-independent manner. Here five laboratories independently set out to test the BC1-FMRP model. We report that specific BC1-FMRP interactions could be documented neither in vitro nor in vivo. Interactions between BC1 RNA and FMRP target mRNAs were determined to be of a nonspecific nature. Significantly, the association of FMRP with bona fide target mRNAs was independent of the presence of BC1 RNA in vivo. The combined experimental evidence is discordant with a proposed scenario in which BC1 RNA acts as a bridge between FMRP and its target mRNAs and rather supports a model in which BC1 RNA and FMRP are translational repressors that operate independently. fragile X syndrome | non-protein-coding RNAs | translational control

The relative strengths and limitations of the three new methods that are designed to identify the RNA-binding proteins (RBP)-RNA interactions are discussed. The development of CLIP, PAIR and trimolecular fluorescence has helped in understanding the RBP-RNA interactions that occur in cells and will thus help define the human interactome.

Translational control at the synapse is thought to be a key determinant of neuronal plasticity. How is such control implemented? We report that small untranslated BC1 RNA is a specific effector of translational control both in vitro and in vivo. BC1 RNA, expressed in neurons and germ cells, inhibits a rate-limiting step in the assembly of translation initiation complexes. A translational repression element is contained within the unique 3' domain of BC1 RNA. Interactions of this domain with eukaryotic initiation factor 4A and poly(A) binding protein mediate repression, indicating that the 3' BC1 domain targets a functional interaction between these factors. In contrast, interactions of BC1 RNA with the fragile X mental retardation protein could not be documented. Thus, BC1 RNA modulates translation-dependent processes in neurons and germs cells by directly interacting with translation initiation factors.

Protein arginine methylation represents a unique signaling system that is considered to be long-term and irreversible. The discovery of a means for eucaryotic cells to remove pot-transitional methyl marks on proteins brings arginine methylation into the mainstream of cell signaling.

The protein modeling, chemical modification, and enzymatic assays were used to study the select exon 15-encoded N-terminal site-directed mutants and also determine the role of the putative conformational switch in arginine methylation. The data obtained supports a novel model for fragile X mental retardation protein (FMRP) arginine methylation in the RG-rich region and the structural changes in [beta]-sheet due to mutating R(507) in the conformation switch to K.

A study was conducted to map the region of methylation to the C-terminal arginine-glycine-rich residues encoded by fragile X mental retardation (FMR1) exon 15. The results suggest that truncating 13 additional amino acids in the smallest alternatively spliced variant of FMR1 exon 15, reduced methylation by more than 85%.