Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

(S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamide analogs with modifications at positions C2 and C5.

Analogs of salinosporamide A with variations of the C2 and C5 substituents are prepared in 8-10 steps using as the first and key transformation a diastereoselective Mukaiyama aldol reaction between the chiral 5-tert-butyldimethylsiloxy-3-methyl-1H-pyrrole-2-carboxylic ester depicted and various aldehyde substrates, promoted by tert-butyldimethylsilyl triflate. In this transformation, the 4-trimethylsilyl-3-butyn-2-ol ester functions to direct the formation of predominantly one of four possible diastereomeric aldol products. Introduction of the C2 appendage by a later-stage, stereocontrolled alkylation reaction permits the construction of analogs variant at this position. Results from in vitro and cell-based assays of proteasomal inhibition are reported. Mass spectrometric studies provide mechanistic details of proteasomal modification by salinosporamide A and analogs.

Molecular structure and concentration of melanin in the stratum corneum of patients with melasma.

Melasma is an abnormal acquired hyperpigmentation of the face of unknown origin, it is considered a single disease and very little has been found regarding its pathogenesis. It is usually assumed that melasma is due to excessive melanin production, but excessive retention or abnormal metabolism of this molecule has not yet been considered. In order to search for an alternate explanation for the excessive pigmentation in melasma the molecular structure and concentration of melanin in the stratum corneum of patients with melasma was analyzed using Raman spectroscopy and optical transmission spectroscopy, respectively. From this study it became apparent that in melasma melanin is concentrated in the deeper layers of the skin but its exteriorization remains the same as for healthy skin. Raman spectroscopy measurements showed degraded molecules of melanin in some subjects, which may help explain the variable success rate of the standard therapy.

Use of lithium hexafluoroisopropoxide as a mild base for Horner-Wadsworth-Emmons olefination of epimerizable aldehydes.

[reaction: see text] The weak base lithium 1,1,1,3,3,3-hexafluoroisopropoxide (LiHFI) is shown to be highly effective as a reagent for intermolecular Horner-Wadsworth-Emmons (HWE) olefination of epimerizable aldehydes with trimethyl phosphonoacetate, affording products with little or no epimerization and notably high E-selectivity.

@-tides as reporters for molecular associations.

The 1,6-dihydro-3(2H)-pyridinone unit is an amino acid surrogate that favors the extended beta-strand conformation when incorporated in an oligopeptide ("@-tide") strand. We now report that the circular dichroism (CD) signature of the vinylogous amide in the @-unit is sensitive to conformation in organic and aqueous solvents and, therefore, is useful as a quantitative measure of @-tide association and folding processes that involve this moiety. Moreover, this method can be employed in the micromolar concentration range, which is not readily accessible using other techniques. Measurements of @-tide dimerization and beta-hairpin folding equilibria not only demonstrate the utility and generality of this approach but also provide a way to quantify amino acid side chain-side chain interactions relevant to beta-sheet stability.

@-Tide-stabilized beta-hairpins.

As minimalist versions of beta-structure, two-stranded beta-hairpins are commonly employed as platforms for assessing the interactions that stabilize beta-sheets in proteins. We have found that the presence of a 1,6-dihydro-3(2H)-pyridinone moiety (the "@-unit") as an amino acid replacement at the i - 1 or i + 4 positions relative to a beta-turn strongly stabilizes the hairpin conformation. Hybrids of this type bridge the gap between natural beta-hairpins and unnatural beta-sheets because the @-unit only replaces one residue in a peptide while stabilizing the hairpin conformation to a greater extent than a normal amino acid. In this report, we describe the synthesis of a variety of @-tide-templated hairpins and the NMR and CD characterization of their conformations in both polar and nonpolar solvents.

Ocular lens NAD kinase: partial purification and metabolic implications.

The ocular lens displays a significant amount of NADP(H) dependent metabolic traffic, but the origin of this cofactor has not been established. Size exclusion chromatography of bovine lens crude extract on a Sephacryl S300-HR column fitted with an eluate concentrator revealed two bands with NAD kinase activity, based on enzymatic cycling with signal amplification of the column fractions using a Cobas-Fara II centrifugal fast analyzer. Ve/Vo ratios from the chromatographic runs suggest that the relative molecular weight values lie within the ranges 8.91-3.98 x 10(5) and 2.04-1.26 x 10(5), respectively, for these two bands. An approximately 10-fold enhancement of enzyme activity over the crude fraction is realized from the chromatography step. Results point to NAD kinase as the source generator of this anchoring and linking cofactor for the oxidative stress and pentose phosphate enzyme systems, respectively.