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。在过去的一年中，本节的成员接纳了大约60名膀胱症患者进入NIH临床研究中心，主要是门诊病人，记录了口服cysteamine治疗在生长，肾功能和眼质异常方面的有益作用。此外，他们描述了泰国囊肿病患者中的CTN突变，对伴随着伴随着伴随的囊肿作品进行了权威审查，并介绍了儿科肾病学家和囊这症倡导组的国家和国际会议。与国家眼科研究所的一致，科医师协助一家制药公司获得了FDA的新药认可，以获得Cysteamine Eyedrops，该公司现已在商业上可用。 EyeDrops含有抑制性药物Cysteamine，科学家和合作者发现使用人和鼠模型抑制胰腺癌的扩散。该部分继续充当囊肿性的国际权威，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。本节的成员与NCI皮肤科医生合作，将红棕色丘疹描述为该疾病的表现特征。他们继续计划使用尼定酮，尼炎是一种产生均匀酸的酶的强大抑制剂，并为全世界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。在过去的一年中，本节的成员报告了世界上仅有HPS-8的第二个家庭，以及HPS-2患者中间质肺疾病和淋巴细胞淋巴淋巴结症的发生。部分研究人员还表征了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，专家本年度对HPS进行了两次权威评论，一项关于遗传学的评论，另一篇是有关治疗的评论。 4。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200多名ARPKD/CHF和相关纤毛病患者。该小组最近描述了ARPKD的先天性肝纤维化，并开始对相关的纤毛病Alstrom综合征进行了深入研究。本节的成员充当了ARPKD/CHF和其他Ciliopathies的临床方面的国家当局。 5。科学家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，为全世界患者提供了分子诊断。研究人员已经描述了Griscelli综合征3型的极为罕见的临床和细胞发现。它们继续表征具有神经学表现的温和chd患者的临床，分子和细胞方面，而NCATS研究者则使用小分子治疗和小鼠模型的Neurology neurology Suneings进行了小分子疗法的神经学症状。 6。一个部分研究人员管理了一项临床方案，该方案遵循数十名白化病亚型的患者。这项研究提供的临床和分子研究使他成为了美国关于这种疾病的权威，他已经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研究者合作，以治疗肾上腺素酮人类的部分白化病的方案，以提高血浆酪氨酸水平并提供眼睛色素以增强视力。 7。研究人员已成为唾液酸合成的世界专家，其限速步骤是由GNE催化的，GNE是由基因GNE编码的双功能酶。双重性gne突变患者会出现gne肌病，这是一种晚发神经肌肉疾病。 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.本节的成员还为临床遗传学界的唾液酸储存疾病撰写了权威综述。 8。与稀有疾病研究办公室和NIH临床中心合作，该节的成员领导NIH未诊断的疾病计划（UDP）。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8000多次查询和3000个病历。 UDP使用下一代遗传技术，并作为将个性化药物带入罕见病患者的模型。该计划已接受650多名患者，并接受了600多名患者，在每种情况下都提供了最先进的临床研究，并解决了大约150个诊断困境，其中一些是极为罕见的疾病。 UDP研究人员还确定了大约50种新疾病的候选基因，并通过细胞和生化研究来展示基本缺陷。 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淀粉样肌病，由于缺陷的维生素D 24-羟化酶和早期发作肌病而引起的肾石岩症，通过SNP和Exome序列分析诊断出诊断为诊断为诊断的肌病，呼吸困难和吞咽困难（EMARDD）。 UDP还发表了有关特征良好的外显子的系统识别，并写了5篇描述UDP工作的论文。 UDP领导者在世界各地的UDP上进行了25次讲座和研讨会，并获得了7年的资金，以扩展该计划到外壁外场地。基于此支持，部分成员组织了新鉴定的可能导致新疾病的变种的基因功能研究的缩合，并建立了培训课程，以分析SNP阵列和外显子组测序结果。 9。本节的其他追求包括在子宫铜疗法中的合作，在常染色体隐性类型的肾上腺素钙化类型中发现遗传缺陷，描述由于petf3b基因的临床表型SATB2的相互作用，SATB2的相互作用，以及peter erdepter of ers of患者的临床表型。 科学家还合作鉴定了由于VPS45中双重突变而导致的新先天性中性粒细胞缺陷综合征，该突变通过内体系统调节膜运输。