Human Biochemical Genetics

人类生化遗传学

• 批准号: 8149428
• 负责人: William Gahl
• 金额: $ 370.77万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149428
• 关键词: Address; Adenosine; Advocacy; Affect; Alpha Granule; Biochemical Genetics; Breast Cancer Cell; CCL2 gene; Candidate Disease Gene; Caring; Characteristics; Coagulation Process; Cyst; Cysteamine; Cystinosis; Cytoplasmic Granules; Data; Diagnosis; Disease; Disease susceptibility; Enrollment; Enzyme Inhibitors; Enzymes; Epilepsy; Etiology; Eyedrops; Fibrosis; Genes; Human; Molecular; Mutation Spectra; New Drug Approvals; Other Genetics; Pharmaceutical Preparations; Placebo Control; Randomized; Study Section; Vascular Endothelial Cell; gene therapy

Summary: The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to provide insight into cellular mechanisms and to care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 50 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they wrote a nephrology book chapter on cystinosis and described the craniofacial and dental findings of the disease, collaborated on an investigation of mitochondrial autophagy in cystinotic cells, addressed national meetings of cystinosis advocacy groups, and assisted in the submission of a New Drug Approval application to the FDA for cysteamine eyedrops. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continued its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Members of the group described the mutation spectrum in homogentisic acid oxygenase (HGD), the gene involved in alkaptonuria. Members of the Section are writing a paper on the results of a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and they continue to provide their expertise for patients and physicians throughout the world. 3. The Section remains the only center in the world investigating both the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles, including melanosomes in melanocytes and dense bodies in platelets. There are 8 genetic subtypes of this disease and, by investigating more than 270 affected individuals, members of the Section have determined that the fatal pulmonary fibrosis of HPS occurs only in subtypes 1, 2 and 4. The Sections work has identified novel HPS1 mutations in Puerto Rican, Indian, and African American patients, and has described the clinical characteristics of HPS-6. Members of the group also identified the promoter regions of HPS genes and described abnormal cytokine patterns in HPS alveolar macrophages. Physicians in the group are writing a report on their randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. In an ancillary pilot study, patients with severe, fatal pulmonary fibrosis are being treated with a 5-drug regimen in an attempt to arrest their disease; three patients have been enrolled. In parallel with these clinical trials, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokine markers and surface glycoproteins in blood and pulmonary lavage fluid. Elevations in MCP1, MUC-1, and galectin-3 have been found to signal a decline in pulmonary function. Finally, members of the Section have written a GeneReviews summary of HPS and other disorders of lysosome-related organelles. 4. The Section has mapped the gene for Gray Platelet Syndrome (GPS), a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. Candidate genes continue to be sequenced. Members of the Section have also elucidated the proteome of the alpha granules of platelets, and have provided data that demonstrate that Gray Platelet Syndrome platelets have ghost membranes that lack certain endogenously derived proteins. 5. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF), along with other ciliopathies, to define the natural history and molecular bases of these disorders. More than 100 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group has published papers describing the radiologic features of ARPKD/CHF, correlations of cyst size and renal function in ARPKD/CHF, MKS3 gene mutations in patients with clinical features of other ciliopathies, and PKHD1 sequence variations in 78 patients with ARPKD/CHF. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 6. Members of the Section characterized the oral and craniofacial findings in children with Hutchinson-Gilford Progeria Syndrome. 7. Members of the Section continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome. CHD, a disorder characterized by large intracellular granules and a tendency toward fatal infections, is extremely rare, but the Section has now described paternal heterodisomy in one affected child, as well as classical CHD in an African American infant. They have also identified a novel deletion in the RAB27A gene resulting in Griscelli Syndrome type 2. 8. Section investigators have contributed to the description of a new genetic disorder of epilepsy, ataxia, sensorineural deafness and renal tubulopathy due to mutations in KCNJ10, to the use of glyceryl triacetate for Canavans disease, to the mitochondrial localization of the OPA3 protein in cells of patients with 3-methylglutaconic aciduria, to the use of gene therapy with GNE delivered by Lipoplex particles for Hereditary Inclusion Body Myopathy, to the demonstration that polyphosphates within platelet dense granules promote inflammation and coagulation, and to the discovery that secreted RAB27B, small GTPase associated with vesicle membranes, promotes breast cancer cell invasion. 9. In collaboration with the Office of Rare Disease Research and the NIH Clinical Center, the Section has spearheaded a new NIH Undiagnosed Diseases Program. This initiative aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. To date, the Program has received more than 3400 inquiries and 1200 sets of medical records from throughout the country. The Program has accepted more than 330 patients and admitted approximately 220, providing state-of-the-art clinical investigations in every case, and solving approximately 30 diagnostic dilemmas. One new disease has been discovered, involving arterial joint calcifications due to deficiency of the vascular endothelial cell enzyme that converts AMP to adenosine and inorganic phosphate. This disease reveals the critical role of adenosine in inhibiting default calcification in vascular cells.

概括： 人类生物化学遗传学研究部分选择了代谢和其他遗传疾病的先天错误，以洞悉细胞机制，并照顾被忽视的罕见疾病患者的群体。 1。本节的成员接纳了大约50名膀胱变性的人作为NIH临床研究中心的住院或门诊病人，记录了口服cysteamine治疗在生长，肾功能和眼科异常方面的有益作用。此外，他们撰写了肾脏学书籍一章有关囊肿性的书籍，并描述了该疾病的颅面和牙齿发现，并合作研究了囊肿细胞中线粒体自噬的调查，介绍了Cystinoiss倡导组的全国性会议，并协助向Fda Enepops提出新药的应用程序，以提出新药的申请。该部分是膀胱疾病的世界权威，每年对全世界患者和医生的数十次询问做出回应。 2。该部分继续研究烷酸核尿尿症，这是由于缺乏均匀剂量1,2-二氧酶而导致均匀酸的积累障碍。该组的成员描述了与烷基蛋白尿相关的基因均匀酸氧酶（HGD）中的突变光谱。本节的成员正在撰写一篇论文，介绍了尼定酮随机临床试验的结果，尼定酮是一种强大的酶抑制剂，该酶产生同质酸，并继续为世界各地的患者和医生提供专业知识。 3.本节仍然是世界上唯一的中心，该部分研究了Hermansky-Pudlak综合征（HPS）的临床和基本方面，这是一种罕见的眼皮白化病和由于包括黑素细胞和血小板中的梅拉氏菌体的异常形成，包括异常的细胞内囊泡，包括异常的细胞内囊泡。该疾病有8种遗传亚型，通过研究270多个受影响的人，本节的成员确定HPS的致命肺纤维化仅发生在1、2和4的亚型中。这些部分的工作已经确定了波多黎各，印度，印度和非裔美国人患者的新型HPS1突变，并描述了HPS-6的临床特征。该组的成员还鉴定了HPS基因的启动子区域，并描述了HPS肺泡巨噬细胞中的异常细胞因子模式。该小组的医师正在撰写有关抗纤维化剂Pirfenidone的随机，安慰剂对照的临床试验的报告，以抵抗HPS的致命肺纤维化。在一项辅助试点研究中，正在用5药治疗治疗严重的致命肺纤维化患者，以试图阻止其疾病。三名患者已入学。与这些临床试验同时，医师正在研究血液和肺灌洗液中的细胞因子标志物和表面糖蛋白的研究，研究了肺纤维化的病因。发现MCP1，MUC-1和Galectin-3的升高表明肺功能下降。最后，本节的成员撰写了HPS和其他与溶酶体相关细胞器的疾病的Genereviews摘要。 4。该部分已映射了灰色血小板综合征（GPS）的基因，该疾病中缺乏血小板α颗粒，患者患有出血性素质。候选基因继续进行测序。本节的成员还阐明了血小板的α颗粒的蛋白质组，并提供了数据，这些数据表明灰色血小板综合征血小板的幽灵膜缺乏某些内源性衍生的蛋白质。 5。正在进行的临床方案研究常染色体隐性多囊肾脏疾病和先天性肝纤维化（ARPKD/CHF）以及其他纤毛病，以定义这些疾病的自然史和分子碱基。在本研究中，已经评估了100多名ARPKD/CHF和相关纤毛病患者。该小组发表了描述ARPKD/CHF的放射学特征，ARPKD/CHF中囊肿大小和肾功能的相关性，其他纤毛病的临床特征患者的MKS3基因突变以及PKHD1序列序列变化的78例ARPKD/CHF患者。本节的成员充当了ARPKD/CHF和其他Ciliopathies的临床方面的国家当局。 6。本节的成员表征了Hutchinson-Gilford progeria综合征儿童的口腔和颅面发现。 7。本节的成员继续研究囊泡形成和贩运的疾病，例如Chediak-Higashi病（CHD）和Griscelli综合征。冠心病是一种以大细胞内颗粒和致命感染趋势的疾病，极为罕见，但是该部分现在描述了一个受影响的儿童的父亲异疾病，以及非裔美国婴儿的经典冠心病。 They have also identified a novel deletion in the RAB27A gene resulting in Griscelli Syndrome type 2. 8. Section investigators have contributed to the description of a new genetic disorder of epilepsy, ataxia, sensorineural deafness and renal tubulopathy due to mutations in KCNJ10, to the use of glyceryl triacetate for Canavans disease, to the mitochondrial localization of the OPA3 protein in cells of patients with 3-methylglutaconic aciduria, to the use of gene therapy with GNE delivered by Lipoplex particles for Hereditary Inclusion Body Myopathy, to the demonstration that polyphosphates within platelet dense granules promote inflammation and coagulation, and to the discovery that secreted RAB27B, small GTPase associated with vesicle membranes, promotes breast cancer cell invasion. 9。与稀有疾病研究办公室和NIH临床中心合作，该部分率领新的NIH未诊断疾病计划。该计划旨在为具有长期以来诊断的神秘疾病的患者提供答案，并促进有关罕见和常见疾病的医学知识。迄今为止，该计划已从全国各地收到了3400多次查询和1200套病历。该计划已接受330多名患者，并接受了大约220名患者，在每种情况下都提供了最新的临床研究，并解决了大约30个诊断困境。由于血管内皮细胞酶缺乏，将AMP转化为腺苷和无机磷酸盐，涉及一种新的疾病，涉及动脉关节钙化。该疾病揭示了腺苷在抑制血管细胞中默认钙化中的关键作用。