| 1. |
- Burke, Derek G., et al.
(författare)
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Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes
- 2013
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 36:5, s. 869-872
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Tidskriftsartikel (refereegranskat)abstract
- Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal beta-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue. Here, we assessed brain GBA2 enzymatic activity in wild type, heterozygote and GBA1 deficient mice. Additionally, we determined activity in leucocytes obtained from 13 patients with Gaucher disease, 10 patients with enzymology consistent with heterozygote status and 19 controls. For wild type animals, GBA2 accounted for over 85 % of total brain GBA activity and was significantly elevated in GBA1 deficient mice when compared to heterozygote and wild types (GBA1 deficient; 92.4 +/- 5.6, heterozygote; 71.5 +/- 2.4, wild type 76.8 +/- 5.1 nmol/h/mg protein). For the patient samples, five Gaucher patients had GBA2 leucocyte activities markedly greater than controls. No difference in GBA2 activity was apparent between the control and carrier groups. Undetectable GBA2 activity was identified in four leucocyte preparations; one in the control group, two in the carrier group and one from the Gaucher disease group. Work is now required to ascertain whether GBA2 activity is a disease modifying factor in Gaucher disease and to identify the mechanism(s) responsible for triggering increased GBA2 activity in GBA1 deficiency states.
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| 2. |
- Pangrazio, Alessandra, et al.
(författare)
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SNX10 mutations define a subgroup of human Autosomal Recessive Osteopetrosis with variable clinical severity.
- 2013
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 1523-4681. ; 28:5, s. 1041-9
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Tidskriftsartikel (refereegranskat)abstract
- Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than half of ARO cases. Afterwards, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the Sorting Nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in three consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in 3 cases of "Västerbottenian osteopetrosis", named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the RANKL, RANK and OSTM1-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by Hematopoietic Stem Cell Transplantation (HSCT). These results confirm the involvement of SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand SNX10 role in osteoclast physiology and verify whether this protein might be considered a new target for selective anti-resorptive therapies. © 2012 American Society for Bone and Mineral Research.
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| 3. |
- Weinreb, Neal J, et al.
(författare)
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Gaucher disease type 1 : revised recommendations on evaluations and monitoring for adult patients.
- 2004
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Ingår i: Semin Hematol. - 0037-1963. ; 41:4 Suppl 5, s. 15-22
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- For patients with type 1 Gaucher disease, challenges to patient care posed by clinical heterogeneity, variable progression rates, and potential permanent disability that can result from untreated or suboptimally treated hematologic, skeletal, and visceral organ involvement dictate a need for comprehensive, serial monitoring. An updated consensus on minimum recommendations for effective monitoring of all adult patients with type 1 Gaucher disease has been developed by the International Collaborative Gaucher Group (ICGG) Registry coordinators. These recommendations provide a schedule for comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects of this disease. The initial assessment should include confirmation of deficiency of beta-glucocerebrosidase, genotyping, and a complete family medical history. Other assessments to be performed initially and at regular intervals include a complete physical examination, patient-reported quality of life using the SF-36 survey, and assessment of hematologic (hemoglobin and platelet count), visceral, and skeletal involvement, and biomarkers. Specific radiologic imaging techniques are recommended for evaluating visceral and skeletal pathology. All patients should undergo comprehensive regular assessment, the frequency of which depends on treatment status and whether therapeutic goals have been achieved. Additionally, reassessment should be performed whenever enzyme therapy dose is altered, or in case of significant clinical complication.
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