OBJECTIVE: To study the role of GBA variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. METHODS: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk of iRBD, age at onset (AAO), and conversion rates. RESULTS: GBA variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; p = 1 × 10-10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; p = 3.5 × 10-5), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; p = 0.0015). Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers (p = 0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (p = 0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution. CONCLUSIONS: GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

• MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Genetic Variation MeSH
• Glucosylceramidase genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neurodegenerative Diseases genetics   MeSH
• REM Sleep Behavior Disorder genetics   MeSH
• Disease Progression MeSH
• Aged MeSH
• Age of Onset MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• GBA protein, human MeSH Browser
• Glucosylceramidase MeSH

BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

• Keywords
• GBA, PSAP, Parkinson’s disease, REM sleep behavior disorder, genetics, glucocerebrosidase, saposin C,
• MeSH
• Glucosylceramidase genetics   MeSH
• Humans MeSH
• Parkinson Disease * complications   MeSH
• REM Sleep Behavior Disorder * diagnosis   MeSH
• Saposins genetics   MeSH
• Synucleinopathies * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glucosylceramidase MeSH
• PSAP protein, human MeSH Browser
• Saposins MeSH

The genomic sequence of the porcine (Sus scrofa) glucocerebrosidase (GBA) gene (approximately 5.7 kb), encoding glucocerebrosidase (glucosylceramidase; acid beta-glucosidase; EC 3.2.1.45), was determined and compared with human (Homo sapiens) GBA and GBAP (pseudogene). The porcine gene harbours 11 exons and 10 introns, and the genomic organization is identical with human GBA. The exon sequences, coding for signal peptide and mature protein, show 81% and 90% sequence identity, respectively, with the corresponding human GBA sequences. Short interspersed elements, SINEs (PREs), are present in introns 2, 4 and 7. There is no evidence of a pseudogene in pig. The deduced protein sequence of GBA consists of 39 amino acids of signal peptide (long form) and 497 amino acids of the mature protein; the latter shows 90% sequence identity with the human protein. Four polymorphisms were observed within the porcine gene: insertion/deletion of one of the two SINEs (PREs) in intron 2 (locus PREA); deletion of a 37- to 39-bp stretch in intron 4 (one direct repeat and 5' end of PRE); deletion of a 47-bp stretch in the middle part of PRE in intron 4 (locus PREB); and single-base transition (C-T) in intron 6 (locus HaeIII-RFLP). GBA was assigned to chromosome 4q21 by FISH and was localized to the same region by linkage analysis and RH mapping, i.e., to the chromosome 4 segment where quantitative trait loci for growth and some carcass traits are located.

• MeSH
• Alleles MeSH
• Electrophoresis, Agar Gel MeSH
• Exons MeSH
• Gene Frequency MeSH
• Genetic Linkage MeSH
• Genome MeSH
• Glucosylceramidase genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Introns MeSH
• Cloning, Molecular MeSH
• Short Interspersed Nucleotide Elements MeSH
• Humans MeSH
• Chromosome Mapping MeSH
• Models, Genetic MeSH
• Models, Molecular MeSH
• Polymerase Chain Reaction MeSH
• Polymorphism, Restriction Fragment Length MeSH
• Polymorphism, Genetic MeSH
• Swine MeSH
• Protein Sorting Signals MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Glucosylceramidase MeSH
• Protein Sorting Signals MeSH

BACKGROUND: This study outlines the development of a highly interoperable federated IT infrastructure for academic biobanks located at the major university hospital sites across Germany. High-quality biosamples linked to clinical data, stored in biobanks are essential for biomedical research. We aimed to facilitate the findability of these biosamples and their associated data. Networks of biobanks provide access to even larger pools of samples and data even from rare diseases and small disease subgroups. The German Biobank Alliance (GBA) established in 2017 under the umbrella of the German Biobank Node (GBN), has taken on the mission of a federated data discovery service to make biosamples and associated data available to researchers across Germany and Europe. METHODS: In this context, we identified the requirements of researchers seeking human biosamples from biobanks and the needs of biobanks for data sovereignty over their samples and data in conjunction with the sample donor's consent. Based on this, we developed a highly interoperable federated IT infrastructure using standards such as Fast Healthcare Interoperability Resources (HL7 FHIR) and Clinical Quality Language (CQL). RESULTS: The infrastructure comprises two major components enabling federated real-time access to biosample metadata, allowing privacy-compliant queries and subsequent project requests. It has been in use since 2019, connecting 16 German academic biobanks, with additional European biobanks joining. In production since 2019 it has run 4941 queries over the span of one year on more than 900,000 biosamples collected from more than 170,000 donors. CONCLUSION: This infrastructure enhances the visibility and accessibility of biosamples for research, addressing the growing demand for human biosamples and associated data in research. It also underscores the need for improvements in processes beyond IT infrastructure, aiming to advance biomedical research and similar infrastructure development in other fields.

• Keywords
• Biobanks, Biomedical research, Biosamples, FAIR data sharing, Feasibility search, Federated system, IT infrastructure, Software tools, Technology development,
• MeSH
• Biological Specimen Banks * MeSH
• Biomedical Research MeSH
• Databases, Factual MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• Germany MeSH

Database searches have shown that a part of glucocerebrosidase (GBA) transcripts may originate at an alternative upstream promoter (P2) located 2.6 kb upstream of the known (P1) GBA promoter. The putative alternative transcripts contained one or two extra exons (exon -2 or exons -2, -1, respectively), but the first ATG codon and predicted amino-acid sequence are the same as in the transcript from P1. Luciferase assays confirmed promoter activity of both sites in HepG2 cells: the P1 construct exhibited the highest activity of luciferase (17.82±1.10 relative luciferase units), while the P2 construct reached 3.01±0.43 relative luciferase units. Serial 5' deletions of P2 led to changes in reporter activity, the most prominent decreases were observed in deletion constructs carrying bases -353 to -658, and -353 to -920 (numbered as in NM_001005750.1), respectively. This suggests that the P2 core promoter is contained within the region of -920bp to -1311bp. Three P2 transcription initiation sites were found by 5' RACE at positions 347, 380, and 413bp upstream of the +1 ATG. The expression stability of transcripts from P2, P1 was studied in 20 human tissues and was higher than that of GAPDH and ACTB, which are commonly used as reference housekeeping genes. The P2 contains an unmethylated CpG island, multiple Sp-1 consensus binding sites and, unlike P1, does not contain a TATA box, features all common to the majority of housekeeping gene promoters. We have examined DNA samples from a phenotypically diverse group of twenty Ashkenazi Jewish Gaucher patients homozygous for the common mild mutation N370S. Both P1 and P2, as well as exons -2 and -1, did not contain any sequence variations, with the exception of the known polymorphism rs10908459 found on one allele. The phenotypical differences in the patients were thus not explained by nucleotide variations in both promoters.

• MeSH
• Hep G2 Cells MeSH
• CpG Islands MeSH
• Gaucher Disease enzymology   MeSH
• Glucosylceramidase genetics   MeSH
• Consensus Sequence genetics   MeSH
• Humans MeSH
• Molecular Sequence Data MeSH
• Transcription Initiation Site MeSH
• Gene Order MeSH
• Promoter Regions, Genetic * MeSH
• Gene Expression Regulation * MeSH
• Genes, Reporter genetics   MeSH
• Base Sequence MeSH
• Sequence Deletion MeSH
• Sequence Alignment MeSH
• Gene Expression Profiling MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glucosylceramidase MeSH

Gallbladder atrophy (GBA) is characterised by a reduction in the size and volume of the gallbladder. In human medicine, it is well-established that GBA frequently occurs together with pathologies affecting the gallbladder and pancreas. However, to the best of our knowledge, there is currently a dearth of reported cases of GBA in dogs within the veterinary field. In this study, we present a case report of GBA in a 7-year-old Yorkshire Terrier. The diagnosis of GBA was confirmed using abdominal ultrasonography and advanced imaging techniques, including computed tomography, which were performed over a 4-year period. The patient initially presented with predominantly gastrointestinal symptoms, which were subsequently diagnosed and treated as pancreatitis. Concurrently, a gallbladder nodule and an anomalous structure suspected to be cholelithiasis were identified. However, during the 4-year follow-up, the gallbladder structure regressed, leaving only the presence of the gallbladder nodule. Notably, cholecystectomy was not performed, and apart from pancreatitis-related symptoms, the patient did not show any gallbladder-related problems throughout the spontaneous atrophic process. Based on these findings, we propose that the observed GBA was likely induced by cholecystitis associated with pancreatitis. This case underscores the significance of considering GBA as a potential diagnosis in canine patients presenting with pancreatitis and gastrointestinal symptoms. Furthermore, it highlights the value of comprehensive diagnostic imaging in accurately determining the underlying cause of these symptoms.

• Keywords
• cholecystitis, cholelithiasis, computed tomography, gastroinetstinal symptom, nodule,
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Cutaneous collagenous vasculopathy (CCV) is an extremely rare acquired microangiopathy of unknown etiology. The authors describe a case of a 68-year-old man, a carrier of a heterozygous pathogenic variant of the glucocerebrosidase (GBA) gene, who was diagnosed with CCV, revealing uncommon fibrinogen positivity in direct immunofluorescence. The patient was subsequently diagnosed with multiple myeloma. Treatment of the myeloma with combined chemotherapy including bortezomib, followed by autologous stem cell transplantation, led to significant reduction of cutaneous lesions. To the best of the authors' knowledge, this is the first published case of CCV in a carrier of a pathogenic variant of the GBA gene, associated with multiple myeloma and with significant regression of CCV after myeloma treatment. Direct immunofluorescence examination revealed an unusual fibrinogen deposition. Hypothetical causative role of bortezomib treatment was proposed regarding significant regression of CCV.

• Keywords
• bortezomib, cutaneous collagenous vasculopathy, direct immunofluorescence, glucocerebrosidase gene, multiple myeloma,
• MeSH
• Transplantation, Autologous MeSH
• Bortezomib therapeutic use   MeSH
• Fibrinogen therapeutic use   MeSH
• Glucosylceramidase therapeutic use   MeSH
• Skin Diseases, Vascular * pathology   MeSH
• Humans MeSH
• Multiple Myeloma * complications   drug therapy   genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged MeSH
• Telangiectasis * pathology   MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Bortezomib MeSH
• Fibrinogen MeSH
• Glucosylceramidase MeSH

• Keywords
• LIPOIDOSIS *,
• MeSH
• Gaucher Disease * MeSH
• Humans MeSH
• Lipidoses * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The lamins are components of nuclear lamina and they have a profound influence on nuclear structure and functions. They are encoded by three genes, LMNA, LMNB1 and LMNB2. A genomic fragment of the porcine LMNA gene (822 bp; from exons 7 to 9) was amplified by polymerase chain reaction and comparatively sequenced. Four single nucleotide polymorphisms (SNPs) were identified in intronic sequences: G162A, G208A, T367G and C618T. The SNPs are within the restriction sites for enzymes Bsh1236I, HpaII, AluI and Bsh1236I respectively. Allele frequencies at SNPs G208A, T367G and C618T were determined by using eight pig breeds. Linkage analysis in the Hohenheim Meishan x Piétrain family placed the LMNA gene in the chromosome 4q linkage group, between MEF2D and GBA (MEF2D - 3.0 cM - LMNA - 0.2 cM - GBA). In radiation hybrid mapping LMNA was most significantly linked to SW270 on chromosome 4 (39 cR; LOD = 7.86). The LMNA gene is located in the quantitative trait loci region for some carcass traits on chromosome 4q.

• MeSH
• Alleles MeSH
• Genetic Linkage genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Lamin Type A genetics   MeSH
• Radiation Hybrid Mapping veterinary   MeSH
• Swine genetics   MeSH
• Chromosomes, Mammalian genetics   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Lamin Type A MeSH

• MeSH
• Blood Chemical Analysis MeSH
• Electroencephalography MeSH
• Gaucher Disease epidemiology   MeSH
• Infant MeSH
• Humans MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH