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名胱氨酸病患者，其中大部分是门诊患者，记录了口服半胱胺治疗在生长、肾功能和眼科异常方面的有益效果。此外，他们描述了泰国胱氨酸病患者的CTNS突变，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演讲。与国家眼科研究所合作，科医生帮助一家制药公司获得了FDA对半胱胺眼药水的新药批准，这种眼药水现在已经上市了。这种眼药水含有消耗半胱氨酸的药物半胱胺，该药物是由该部门的科学家和合作者通过人类和小鼠模型发现的，可以抑制胰腺癌的扩散。该科继续作为胱氨酸病方面的国际权威机构，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。与NCI皮肤科医生合作，该科成员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nitisinone，一种产生均质酸的酶的强效抑制剂，并向全世界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。在过去的一年中，该科成员仅报道了世界上第二个HPS-8家族，以及HPS-2患者间质性肺疾病和噬血细胞性淋巴组织细胞增多症的发生。部分研究人员还描述了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，科专家撰写了两篇关于HPS的权威评论，一篇是关于遗传学的，一篇是关于治疗的。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。本研究对200多例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，并开始了对相关纤毛病Alstrom综合征的深入研究。该科成员是ARPKD/CHF和其他纤毛病临床方面的国家权威。5. 科科学家继续研究囊泡形成和运输障碍，如chdiak - higashi病（CHD）和Griscelli综合征，为世界各地的患者提供分子诊断。研究人员描述了一个极其罕见的格里塞利综合征3型病例的临床和细胞发现。他们继续研究具有神经系统症状的轻度冠心病患者的临床、分子和细胞特征，并与NCATS研究人员一起，使用小分子疗法和显示神经系统发现的小鼠模型来治疗冠心病的神经系统症状。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。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，他还撰写了关于白化病基因中所有分子突变的最新进展。他正在与NEI的研究人员合作，制定一项用尼替西酮治疗人类部分白化病的方案，以增加血浆酪氨酸水平，并提供眼色素以增强视力。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。该科成员提交了一项低羟化生物标志物的专利，将唾液酸合成缺陷（由于GNE突变）的小鼠作为肾小球疾病模型，证明小鼠GNE肌病的肌肉和肾小球疾病可以通过口服单糖治疗逆转，并描述了小鼠GNE酶的结构同型异构体。该科成员还为临床遗传学界撰写了关于唾液酸积存病的权威综述。8. 与罕见病研究办公室和美国国立卫生研究院临床中心合作，该科成员领导美国国立卫生研究院未确诊疾病项目（UDP）。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。迄今为止，该方案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。该项目已经接收了650多名患者，并接纳了600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。来自UDP的出版物包括与PRF1突变相关的病毒后共济失调，麦尔糖淀粉酶纯合突变，导致常染色体显性白质营养不良的LMNB1重复，孤立生长衰竭的卡恩斯-塞尔综合征，导致遗传性痉挛性截瘫43型的C19orf12突变，罕见的淀粉样肌病，由维生素D 24-羟化酶缺陷引起的肾结石，以及早发性肌病，反射性松弛。通过SNP和外显子组序列分析诊断呼吸窘迫和吞咽困难（EMARDD）。UDP还发表了关于系统识别特征良好的外显子的文章，并撰写了5篇描述UDP工作原理的论文。UDP领导人在世界各地举办了25场关于UDP的讲座和研讨会，并获得了7年的资金，用于将该计划扩展到校外地点。基于这种支持，科成员组织了新发现的可能导致新疾病的变异基因功能研究的签约，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在Menkes病的子宫内铜治疗方面的合作，发现常染色体隐性肾钙化症的遗传缺陷，描述由于蛋白质SATB2与UPF3B基因相互作用而引起的临床表型，以及展示患有erdhem - chester病的患者的PET图像。该组科学家还合作鉴定了由VPS45双等位基因突变引起的一种新的先天性中性粒细胞缺陷综合征，VPS45通过内体系统调节膜运输。

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.