Human Biochemical Genetics

人类生化遗传学

• 批准号: 8750676
• 负责人: William Gahl
• 金额: $ 356.41万
• 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/8750676
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Address; Advocacy; Albinism; Alkaptonuria; Alpha-glucosidase; Alstrom syndrome; Amyloid; Ataxia; Autosomal Recessive Polycystic Kidney; Basic Science; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biological Markers; Blood Platelets; Candidate Disease Gene; Caring; Cells; Cellular biology; Childhood; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Communities; Contracts; Copper; Country; Cysteamine; Cystine; Cystinosis; Defect; Deglutition Disorders; Dermatologist; Diagnosis; Diagnostic; Disease; Disease Pathway; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Erdheim-Chester Disease; Exons; Extramural Activities; Eyedrops; Failure; Family; Fibrosis; Funding; Genes; Genetic; Genetic Techniques; Goals; Griscelli Syndrome; Growth; Hemophagocytic Lymphohistiocytoses; Hemorrhage; Hereditary Disease; Hereditary Spastic Paraplegia; Hermanski-Pudlak Syndrome; Homogentisate 1,2-dioxygenase; Homogentisic Acid; Human; Inborn Errors of Metabolism; Individual; International; Interstitial Lung Diseases; Investigation; Kearns-Sayre syndrome; Knowledge; LMNB1 gene; Lead; Legal patent; Liver Fibrosis; Lung; Malignant neoplasm of pancreas; Medical; Medical Records; Medicine; Melanosomes; Membrane Protein Traffic; Menkes Kinky Hair Syndrome; Mission; Modeling; Molecular; Molecular Diagnosis; Monosaccharides; Mus; Mutation; Myopathy; National Eye Institute; Natural History; Nephrocalcinosis; Nephrolithiasis; Neurologic; Neurologic Manifestations; Neuromuscular Diseases; New Drug Approvals; Oculocutaneous Albinism; Oral; Other Genetics; Outpatients; Paper; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Piebaldism; Pigments; Plasma; Positron-Emission Tomography; Protein Isoforms; Proteins; Protocols documentation; Publications; Publishing; Rare Diseases; Renal function; Renal glomerular disease; Reporting; Research; Research Personnel; Research Project Grants; Respiratory distress; Scientist; Secure; Sequence Analysis; Sialic Acids; Sialuria; Site; Specimen; Study Section; Symptoms; Syndrome; System; Time; Training; Tyrosine; United States; United States National Institutes of Health; Update; Variant; Vesicle; Viral; Vision; Work; Writing; authority; base; chediak-higashi syndrome; ciliopathy; clinical phenotype; early onset; exome sequencing; gene function; in utero; insight; lectures; leukodystrophy; meetings; melanocyte; member; mouse model; neglect; neutrophil; next generation; outcome forecast; programs; research study; small molecule; trafficking

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. In the past year, members of the Section admitted approximately 60 individuals with cystinosis to the NIH Clinical Research Center, largely as outpatients, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they described CTNS mutations in Thai cystinosis patients, wrote authoritative reviews on cystinosis, and addressed national and international meetings of pediatric nephrologists and cystinosis advocacy groups. In concert with the National Eye Institute, Section physicians helped a pharmaceutical company achieve New Drug Approval from the FDA for cysteamine eyedrops, which are now commercially available. The eyedrops contain the cystine-depleting drug, cysteamine, which was found by Section scientists and collaborators to inhibit the spread of pancreatic cancer using human and murine models. The Section continues to serve as an international authority on cystinosis, responding to scores of inquiries 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. In collaboration with NCI dermatologists, members of the Section described red-brown papules as a presenting feature of the disease. They continue to plan for the use of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and 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. In the past year, members of the Section reported only the second family in the world with HPS-8, as well as the occurrence of interstitial lung disease and hemophagocytic lymphohistiocytosis in HPS-2 patients. Section investigators also characterized the molecular interaction between the HPS1 and the HPS4 proteins, and continue to study the cause of the lung fibrosis of HPS. This year, Section experts wrote two authoritative reviews on HPS, one on the genetics and one on treatment. 4. 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 200 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group recently described the congenital hepatic fibrosis of ARPKD and initiated an intense investigation of a related ciliopathy, Alstrom Syndrome. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome, providing molecular diagnoses for patients throughout the world. Investigators have described the clinical and cellular findings in an extremely rare case of Griscelli syndrome type 3. They continue to characterize the clinical, molecular, and cellular aspects of mild CHD patients with neurological manifestations and, with NCATS investigators, pursue treatment of the neurological symptoms of CHD using small molecule therapy and a mouse model that manifests neurological findings. 6. One Section investigator manages a clinical protocol that follows scores of patients with various subtypes of albinism. The clinical and molecular investigations provided by this study make him the United States authority on this disorder, and he has written the current update on all molecular mutations in albinism genes. He is collaborating with NEI investigators on a protocol to treat partial albinism in humans with nitisinone, to increase plasma tyrosine levels and provide ocular pigment to enhance vision. 7. Section investigators have become world experts in sialic acid synthesis, whose rate-limiting step is catalyzed by GNE, a bifunctional enzyme encoded by the gene GNE. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder. Members of the Section submitted a patent for a biomarker for hyposialylation, characterized a mouse with defective sialic acid synthesis (due to mutations in GNE) as a model for glomerular disease, demonstrated that the muscle and glomerular disease of murine GNE myopathy can be reversed by oral monosaccharide therapy, and described the structural isoforms of the murine GNE enzyme. Members of the Section have also written the authoritative review on sialic acid storage diseases for the clinical genetics community. 8. In collaboration with the Office of Rare Diseases Research and the NIH Clinical Center, Members of the Section lead the NIH Undiagnosed Diseases Program (UDP). 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 8000 inquiries and 3000 medical records from throughout the country. The UDP uses next-generation genetic techniques and serves as a model for bringing personalized medicine to rare disease patients. The Program has accepted more than 650 patients and admitted over 600, providing state-of-the-art clinical investigations in every case, and solving approximately 150 diagnostic dilemmas, some of which are extremely rare disorders. UDP investigators have also identified candidate genes for approximately 50 new diseases, and are pursuing demonstration of the basic defects via cellular and biochemical studies. Publications emanating from the UDP include descriptions of post-viral ataxia associated with a PRF1 mutation, homozygous mutations in maltase-glucoamylase, an LMNB1 duplication causing Autosomal Dominant Leukodystrophy, Kearns-Sayre syndrome with isolated growth failure, C19orf12 mutations causing Hereditary Spastic Paraplegia Type 43, a rare amyloid myopathy, nephrolithiasis due to defective vitamin D 24-hydroxylase, and early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) diagnosed through SNP and exome sequence analysis. The UDP has also published on the systematic identification of well-characterized exons and has written 5 papers describing the workings of the UDP. UDP leaders have delivered 25 lectures and seminars on the UDP throughout the world, and have secured 7 years of funding for expansion of the Program to extramural sites. Based upon this support, Section members have organized the contracting of gene function studies of newly identified variants that may be responsible for new diseases, and have established a training course for the analysis of SNP array and exome sequencing results. 9. Miscellaneous pursuits of the Section include collaborations on in utero copper therapy for Menkes disease, discovery of the genetic defect in an autosomal recessive type of nephrocalcinosis, description of a clinical phenotype due to interaction of a protein, SATB2, with the UPF3B gene, and presentation of PET images of a patient with Erdheim-Chester disease. Section scientists also collaborated on the identification of a new congenital neutrophil defect syndrome due to biallelic mutations in VPS45, which regulates membrane trafficking through the endosomal system.

人类生化遗传学部分的研究选择了代谢先天性错误和其他遗传性疾病，以深入了解细胞机制并照顾被忽视的罕见疾病患者群体。 1. 去年，该部门的成员将大约 60 名胱氨酸中毒患者收治到 NIH 临床研究中心，大部分为门诊患者，记录了口服半胱胺治疗对生长、肾功能和眼科异常的有益效果。此外，他们还描述了泰国胱氨酸病患者的 CTNS 突变，撰写了有关胱氨酸病的权威评论，并在儿科肾病专家和胱氨酸病倡导团体的国内和国际会议上发表了讲话。该部门的医生与国家眼科研究所合作，帮助一家制药公司的半胱胺滴眼剂获得了 FDA 的新药批准，该滴眼剂现已上市。这些眼药水含有胱氨酸消耗药物半胱胺，该部门的科学家和合作者利用人类和小鼠模型发现这种药物可以抑制胰腺癌的扩散。该科继续作为胱氨酸病的国际权威，每年都会答复来自世界各地患者和医生的大量询问。 2. 该科继续对尿黑酸尿症进行调查，尿黑酸尿症是一种因尿黑酸 1,2-双加氧酶缺乏而导致尿黑酸蓄积的疾病。该部门的成员与 NCI 皮肤科医生合作，将红棕色丘疹描述为该疾病的一个表现特征。他们继续计划使用尼替西农（一种产生黑黑酸的酶的强大抑制剂），并为世界各地的患者和医生提供他们的专业知识。 3. 该科仍然是世界上唯一研究赫曼斯基-普德拉克综合征（HPS）临床和基础方面的中心，这是一种罕见的眼皮肤白化病和由于细胞内囊泡（包括黑素细胞和致密体中的黑素体）形成异常而出血的疾病在血小板中。去年，该科成员报告了全球第二个HPS-8家族，以及HPS-2患者出现间质性肺病和噬血细胞性淋巴组织细胞增多症。研究人员还表征了HPS1和HPS4蛋白之间的分子相互作用，并继续研究HPS肺纤维化的原因。今年，该科专家撰写了两篇关于 HPS 的权威评论，一篇关于遗传学，一篇关于治疗。 4. 一项正在进行的临床方案调查常染色体隐性多囊肾病和先天性肝纤维化 (ARPKD/CHF) 以及其他纤毛病，以确定这些疾病的自然史和分子基础。本研究对 200 多名 ARPKD/CHF 及相关纤毛病患者进行了评估。该小组最近描述了 ARPKD 的先天性肝纤维化，并开始对相关纤毛病阿尔斯特罗姆综合征进行深入研究。该科的成员是 ARPKD/CHF 和其他纤毛病临床方面的国家权威。 5. 部门科学家继续研究囊泡形成和运输疾病，例如 Chediak-Higashi 病 (CHD) 和 Griscelli 综合征，为世界各地的患者提供分子诊断。研究人员描述了极其罕见的 3 型 Griscelli 综合征病例的临床和细胞发现。他们继续描述具有神经系统表现的轻度 CHD 患者的临床、分子和细胞方面的特征，并与 NCATS 研究人员一起寻求神经系统症状的治疗使用小分子疗法和表现出神经学发现的小鼠模型来治疗冠心病。 6. 一个部门的调查员管理一项临床方案，该方案跟踪患有各种白化病亚型的患者。这项研究提供的临床和分子研究使他成为美国研究这种疾病的权威，他撰写了有关白化病基因所有分子突变的最新更新。他正在与 NEI 研究人员合作制定一项方案，用尼替西农治疗人类部分白化病，以提高血浆酪氨酸水平并提供眼色素以增强视力。 7. 部门研究人员已成为唾液酸合成方面的世界专家，唾液酸合成的限速步骤是由 GNE 催化的，GNE 是一种由 GNE 基因编码的双功能酶。具有双等位基因 GNE 突变的患者会出现 GNE 肌病，这是一种迟发性神经肌肉疾病。该部门的成员提交了一项低唾液酸化生物标志物的专利，以唾液酸合成缺陷（由于 GNE 突变）的小鼠为肾小球疾病模型，证明小鼠 GNE 肌病的肌肉和肾小球疾病可以通过以下方法逆转：口服单糖疗法，并描述了鼠 GNE 酶的结构亚型。该科成员还为临床遗传学界撰写了关于唾液酸贮积病的权威评论。 8. 该科成员与罕见病研究办公室和 NIH 临床中心合作，领导 NIH 未确诊疾病计划 (UDP)。该倡议旨在为患有长期无法诊断的神秘病症的患者提供答案，并增进有关罕见和常见疾病的医学知识。迄今为止，该计划已收到来自全国各地的 8000 多份咨询和 3000 份医疗记录。 UDP 使用下一代遗传技术，并作为为罕见疾病患者提供个性化医疗的典范。该计划已接收了 650 多名患者，并收治了 600 多名患者，为每个病例提供最先进的临床研究，并解决了大约 150 个诊断难题，其中一些是极其罕见的疾病。 UDP 研究人员还确定了大约 50 种新疾病的候选基因，并正在通过细胞和生化研究来证明基本缺陷。 UDP 发表的出版物包括与 PRF1 突变相关的病毒后共济失调、麦芽糖酶-葡糖淀粉酶纯合突变、导致常染色体显性脑白质营养不良的 LMNB1 重复、伴有孤立性生长障碍的 Kearns-Sayre 综合征、导致 43 型遗传性痉挛性截瘫的 C19orf12 突变相关的描述，一种罕见的淀粉样肌病，由于缺陷导致的肾结石通过 SNP 和外显子组序列分析诊断维生素 D 24-羟化酶、早发性肌病、反射消失、呼吸窘迫和吞咽困难 (EMARDD)。 UDP 还发表了有关特征明确的外显子的系统鉴定的文章，并撰写了 5 篇描述 UDP 工作原理的论文。 UDP 领导人已在世界各地举办了 25 场有关 UDP 的讲座和研讨会，并获得了 7 年的资金将该计划扩展到校外地点。基于这种支持，部门成员组织了新发现的可能导致新疾病的变异的基因功能研究的承包，并建立了 SNP 阵列和外显子组测序结果分析的培训课程。 9. 该科的其他工作包括门克斯病子宫内铜疗法的合作、常染色体隐性肾钙质沉着症遗传缺陷的发现、由于蛋白质 SATB2 与 UPF3B 基因相互作用引起的临床表型的描述，以及埃尔德海姆-切斯特病患者的 PET 图像呈现。 该部门的科学家还合作鉴定了一种新的先天性中性粒细胞缺陷综合征，该综合征是由于 VPS45 的双等位基因突变引起的，VPS45 通过内体系统调节膜运输。