Human Biochemical Genetics

人类生物化学遗传学部分研究选定的先天性代谢错误和其他遗传疾病，以提供对细胞机制的深入了解，并照顾被忽视的罕见疾病患者群体。1. 在过去的一年里，该科的成员向NIH临床研究中心收治了大约60名患有肾病型胱氨酸病的患者，其中大部分是门诊患者，记录了口服半胱胺治疗在生长、肾功能、晚期并发症和眼部异常方面的有益效果。此外，他们撰写了关于胱氨酸病的权威评论，并在儿童肾病学家和胱氨酸病倡导团体的国家和国际会议上发表了讲话。该科继续作为这一疾病的国际权威机构，每年答复世界各地病人和医生提出的许多询问。2. 该科继续调查尿酸症，这是由于缺乏均质酸1,2-双加氧酶引起的均质酸积累紊乱。该科成员正在编写使用nitisinone的临床方案，nitisinone是一种产生均质酸的酶的强效抑制剂，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Hermansky-Pudlak综合征（HPS）临床和基础方面的中心，HPS是一种罕见的皮肤白化病和出血疾病，由于细胞内囊泡的异常形成，包括黑素细胞中的黑素体和血小板中的致密体。在过去的一年里，该部门的成员确定了HPS-1和HPS-4蛋白的特定结构域，这些蛋白相互作用形成溶酶体相关细胞器复合物-3的生物发生，其在细胞内囊泡的运输中起作用。他们与欧洲研究人员合作，证实了HPS-2患者的噬血细胞性淋巴组织细胞增多症的风险，并描述了HPS合并肺纤维化患者的半凝集素-3水平升高。4. 一项正在进行的临床研究研究了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历史和分子基础。本研究评估了200多例ARPKD/CHF及相关纤毛病患者，目前包括Alstrom综合征。今年，该小组撰写了关于先天性肝纤维化的权威综述，他们继续作为ARPKD/CHF和其他纤毛病临床方面的国家权威。5. 切片科学家继续研究Chediak-Higashi病（CHD），最近显示，血小板致密体的电子显微镜反映了骨髓移植在这种疾病中的疗效。6. 一名科研究员管理着一项临床方案，该方案跟踪了数十名不同亚型的白化病患者。今年，他提供了所有已知导致皮肤白化病的突变的权威清单，他是这个疾病的国家权威。7. 部分研究人员已成为世界专家在唾液酸合成，其限速步骤是由基因编码的双功能酶GNE催化。双等位基因基因突变的患者发展为基因e肌病，一种迟发性神经肌肉疾病。在过去的一年里，该科的成员报告了GNE肌病患者细胞中鞘糖脂升高，描述了一种基于循环糖蛋白低甲基化的疾病的新生物标志物，建立了该疾病的新命名法，并将所有已知的引起GNE肌病的突变制成表格。8. 该科成员还领导美国国立卫生研究院未确诊疾病项目（UDP），该项目目前由共同基金支持，作为一个由6个临床站点、一个协调中心和两个测序中心组成的UDP网络。该计划旨在为患有长期无法诊断的神秘疾病的患者提供答案，并促进对罕见和常见疾病的医学知识。美国国立卫生研究院校内研究项目UDP位于人类生化遗传学部分，根据其6年处理来自全国和世界各地的9500多份查询和3300份医疗记录的经验，为未确诊疾病网络（UDN）提供指导。UDP使用下一代基因技术，并作为为罕见病患者提供个性化医疗的典范。该项目已经接受了800多名患者，并接纳了700多名患者，为每个病例提供了最先进的临床调查，并解决了大约150个诊断难题，其中大多数是极其罕见的疾病。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寻求基本缺陷。在过去的一年里，来自UDP的出版物包括LMNB1重复导致常染色体显性白质营养不良，卡恩斯-塞尔综合征伴孤立生长衰竭，C19orf12突变导致遗传性痉挛性截瘫43型，淀粉样肌病罕见病例，维生素D 24-羟化酶缺陷引起的肾结石，早发性肌病，反射性松弛，呼吸窘迫和吞咽困难（EMARDD），通过SNP和外显子组序列分析诊断。grine2a突变导致癫痫性脑病，可通过memantine治疗；HRAS和NRAS的体激活突变导致皮肤和骨骼病变、低磷血症和FGF23升高；一个家族中极为罕见的三种疾病（grine2b突变导致的磷酸烯醇丙酮酸羧激酶缺乏症、Smith-Magenis综合征和NMDA受体谷氨酸不敏感）；以及SPG11和SPG15导致的痉挛性瘫痪。美国国立卫生研究院UDP还发表了关于系统地识别特征明确的外显子、美国和中国在未确诊疾病调查中的文化差异以及NIH UDP患者偶然发现的频率的文章。世卫组织领导人就研究罕见病的重要性撰写了一篇社论，并在世界各地就世卫组织问题举行了25次讲座和研讨会。小组成员签约了新发现的与新疾病相关的变异的基因功能研究，建立了SNP阵列和外显子组测序结果分析的培训课程，并组织了一次罕见和未诊断疾病的国际会议。9. 本节的其他追求包括描述由于蛋白SATB2与UPF3B基因相互作用而引起的临床表型，展示患有erdhem - chester病的患者的PET图像，以及报告患有3-甲基戊二酸尿症III型的兄弟姐妹中新的OPA3突变。该科科学家还合作鉴定了两种新的疾病。他们描述了一种新的先天性中性粒细胞缺陷综合征，这是由VPS45的双等位基因突变引起的，VPS45调节通过内体系统的膜运输。他们还发现了一种新型的肾范可尼综合征，这是由于过氧化物酶体蛋白EHHADH的错误靶向导致线粒体功能受到干扰。

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 nephropathic cystinosis to the NIH Clinical Research Center, largely as outpatients, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, late complications, and ophthalmic abnormalities. In addition, they wrote authoritative reviews on cystinosis, and addressed national and international meetings of pediatric nephrologists and cystinosis advocacy groups. The Section continues to serve as an international authority on the disease, 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. Members of the Section are writing a clinical protocol for the use of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and 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 identified the specific domains of the HPS-1 and HPS-4 proteins that interact with each other to form Biogenesis of Lysosome-related Organelles Complex-3, which functions in the trafficking of intracellular vesicles. They collaborated with European investigators to demonstrate the risk of hemophagocytic lymphohistiocytosis in HPS-2 patients, and described elevated levels of galectin-3 in HPS patients with pulmonary fibrosis. 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, now including Alstrom syndrome, have been evaluated in this study. This year, the group wrote the definitive review on Congenital Hepatic Fibrosis, and they continue to serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate Chediak-Higashi disease (CHD), recently showing that electron microscopy of platelet dense bodies reflects the efficacy of bone marrow transplantation in this disease. 6. One Section investigator manages a clinical protocol that follows scores of patients with various subtypes of albinism. This year, he provided the authoritative listing of all known mutations causing oculocutaneous albinism, and he serves as the nations authority on this disorder. 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. This past year, members of the Section reported elevated glycosphingolipids in cells of GNE myopathy patients, described a new biomarker for the disease based upon hyposialylation of a circulating glycoprotein, established new nomenclature for the disease, and tabulated all the known mutations causing GNE myopathy. 8. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), now supported by the Common Fund as a Network of UDPs with 6 Clinical Sites, a Coordinating Center, and two Sequencing Centers. 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. The NIH Intramural Research Programs UDP, located within the Section on Human Biochemical Genetics, is providing guidance to the Undiagnosed Diseases Network (UDN) based upon its 6 years of experience handling more than 9500 inquiries and 3300 medical records from throughout the country and the world. 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 800 patients and admitted over 700, providing state-of-the-art clinical investigations in every case, and solving approximately 150 diagnostic dilemmas, most of which represent extremely rare disorders. UDP investigators have also identified candidate genes for approximately 50 new diseases, and are pursuing the basic defects via cellular and biochemical studies. In the past year, publications emanating from the UDP include descriptions of an LMNB1 duplication causing Autosomal Dominant Leukodystrophy, Kearns-Sayre syndrome with isolated growth failure, C19orf12 mutations causing Hereditary Spastic Paraplegia Type 43, a rare case of amyloid myopathy, nephrolithiasis due to defective vitamin D 24-hydroxylase, early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) diagnosed through SNP and exome sequence analysis, GRIN2A mutations causing epileptic encephalopathy treatable with memantine, somatic activating mutations in HRAS and NRAS causing cutaneous and skeletal lesions, hypophosphatemia, and elevated FGF23, the extremely rare occurrence of three disorders in one family (phosphoenolpyruvate carboxykinase deficiency, Smith-Magenis Syndrome, and NMDA receptor glutamate insensitivity due to GRIN2B mutations), and spastic paraplegias due to SPG11 and SPG15. The UDP has also published on the systematic identification of well-characterized exons, cultural differences between the United States and China in the investigation of undiagnosed diseases, and the frequency of incidental findings in NIH UDP patients. UDP leaders have written an editorial on the importance of studying rare diseases and have delivered 25 lectures and seminars on the UDP throughout the world. Section members have contracted for gene function studies of newly identified variants associated with new diseases, have established a training course for the analysis of SNP array and exome sequencing results, and have organized an international conference on rare and undiagnosed diseases. 9. Miscellaneous pursuits of the Section include description of a clinical phenotype due to interaction of a protein, SATB2, with the UPF3B gene, presentation of PET images of a patient with Erdheim-Chester disease, and reporting of novel OPA3 mutations in siblings with 3-methylglutaconic aciduria type III. Section scientists also collaborated on the identification of two new diseases. They characterized a new congenital neutrophil defect syndrome due to biallelic mutations in VPS45, which regulates membrane trafficking through the endosomal system. They also discovered a new type of renal Fanconi Syndrome due to interference with mitochondrial function caused by mistargeting of the peroxisomal protein EHHADH.