Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877

Exotic phase transitions in RERhSn compounds

Crystal and magnetic properties of three equiatomic ternary RERhSn compounds (where RE = Ce, Nd, Gd) have been studied by means of X-ray diffraction, ac, and dc magnetic susceptibility measurements, as well as using Mössbauer spectroscopy with 119Sn and 155Gd resonances. CeRhSn does not order magnetically down to 2 K while NdRhSn undergoes ferromagnetic transition at TC = 10.3 K and GdRhSn orders antiferromagnetically below TN = 16 K. Our CeRhSn and NdRhSn samples become superconductive below 6.5 K and 6.9 K, respectively

Ferromagnetic ordering in GdPdCd

GdPdCd was obtained in pure form via reaction of the elements in a sealed tantalum tube in a high-frequency furnace. The structure was investigated by X-ray diffraction on both powders and single crystals: ZrNiAl type, P (6) over bar 2m, a = 758.2(1), c = 391.78(7) pm, wR(2) = 0.0410 for 358 F-2 values and 14 variables. Striking structural motifs of GdPdCd are two types of palladium-centered tricapped trigonal prisms [PdlCd(3)Gd(6)] and [Pd2Cd6Gd3]. Together the palladium and cadmium atoms build a three-dimensional network in which the gadolinium atoms fill distorted pentagonal channels. Susceptibility measurements reveal Curie-Weiss behaviour with an effective magnetic moment of 8.2(1) mu(B)/Gd. GdPdCd orders ferromagnetically at T-C = 62.5 (5) K and shows a saturation magnetization of 7.3 (1) mu(B)/Gd at 4.2 K and 5 T. The thermal variations of hyperfine parameters in GdPdCd were measured over the temperature ran-e from 4.2 to 67 K using Gd-155 Mossbauer spectroscopy. The change of the electric field gradient below the Curie temperature T-C is interpreted by an anomalous thermal expansion associated with magnetostrictive strains. The electronic and magnetic properties of GdPdCd were investigated by TB-LMTO-ASA band structure calculations. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved