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. 该科成员接收了大约60名胱氨酸病患者作为住院或门诊患者到NIH临床研究中心，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，他们还合作发表了描述口服半胱胺治疗毒副作用的出版物。他们还为《欧洲肾脏病学》、《儿童肾脏病学》和《奈特医学插图集》撰写了关于胱氨酸病的权威评论，在胱氨酸病倡导团体的国内和国际会议上发表了演讲，并继续协助国家眼科研究所向胱氨酸病社区提供半胱胺滴眼液。该科是世界上关于胱氨酸病的权威机构，每年对世界各地病人和医生提出的许多询问作出答复。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NHLBI的心脏病专家合作，该科成员描述了尿尿患者主动脉狭窄和动脉钙化的频率。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。在过去的一年里，该科的成员报告了由于基因苍白素的双等位基因突变，在一名男婴中发现了第九种HPS亚型。该基因产物编码溶酶体相关细胞器复合物-1生物发生的一个组成部分，这是一种负责细胞内囊泡形成的蛋白质复合物。该科成员还描述了非波多黎各西班牙裔个体和世界上第二个HPS-8家庭的HPS的临床和分子表现。Sections肺组报道了3例HPS-2患者的间质性肺疾病，记录了这种并发症作为HPS-2表型的一部分。通过对血液和肺灌洗液中半乳糖凝集素-3等表面糖蛋白的研究，研究人员继续研究HPS肺纤维化的病因。在与NIAID研究者的合作下，Section的科学家们正在研究HPS中肥大细胞的功能，因为这些细胞的嗜碱性颗粒是溶酶体样细胞器。该科还合作开展了一个项目，以证明KXD1（一种花相互作用蛋白）在溶酶体相关细胞器的形成中起作用。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。该小组最近发表的论文描述了常染色体显性多囊肾病中ARPKD/CHF和门静脉高压的专性杂合子的肝肾发现。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。在合作中，他们报道了接受和不接受骨髓移植的冠心病患者的血小板致密体结果，并广泛地描述了有神经系统表现的轻度冠心病患者的临床、分子和细胞方面的特征。在与NCATS研究人员的合作下，该科的基础科学家正在利用小分子疗法和显示神经学发现的小鼠模型来治疗冠心病的神经学症状。6. 一位科研究者已经建立了一个临床方案，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调查使他成为美国研究这种疾病的权威。他和他的NEI合作者已经证明，在眼皮肤白化病小鼠模型中，尼替西酮增加血浆酪氨酸水平，改善眼部和皮肤色素沉着异常，为可能的人类治疗铺平了道路。7. 在各种各样的合作追求中，科研究者提供了遗传性包涵体肌病缺陷的GNE基因，静脉注射给患者。其他小组成员已经报道了一例罕见的Smith-Magenis综合征患者和一个分离的RAI1突变，不同组织中UDP-GlcNac 2- epimase /ManNAc激酶的不同同工型，Gne小鼠的肾脏病理，半胱胺在抑制癌症转移中的作用，以及溶酶体膜唾液酸转运蛋白sialin在质膜中作为硝酸盐转运蛋白的事实。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6800多份咨询和2500套医疗记录。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530多名患者，并收治了450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100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20种与遗传变异相关的新疾病，并正在通过细胞和生化研究来证明基本缺陷。来自UDP的出版物包括由于纯合子AFG3L2突变引起的新的痉挛性共济失调神经病综合征的描述，一个非常罕见的脂肪酸羟化酶缺乏和神经变性的复合杂合子病例，一个IgG4硬化性疾病伴乳突炎的病例，一个青少年发病的GM1神经节脂质病的女孩，以及痉挛性截瘫和步态异常患者的脑脊液中神经递质缺乏（SPG11）。UDP还通过发表论文来推进下一代测序分析领域，这些论文描述了用于分析小孟德尔谱系变异的全外显子测序过滤器和工具，假阳性变异和外显子在外显子测序平台中表现良好的清单，与肌肉疾病和痉挛性截瘫相关的基因变异，全外显子序列分析中SNP基因分型的使用。以及使用累积分布函数来分析SNP阵列的镶嵌性量化。最后，在过去的一年里，UDP领导人写了一篇关于该计划的评论和社论。最近，该科领导获得了7年的支持，将该计划扩展到校外地点。

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 60 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 collaborated on publications describing toxic side effects of oral cysteamine therapy. They also wrote authoritative reviews on cystinosis for European Nephrology, Pediatric Nephrology, and the Netter Collection of Medical Illustrations, addressed national and international meetings of cystinosis advocacy groups, and continued to assist the National Eye Institute in the provision of cysteamine eyedrops to the cystinosis community. The Section serves as the world 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 cardiologists in the NHLBI, members of the Section described the frequency of aortic stenosis and arterial calcifications in alkaptonuria. 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 a ninth subtype of HPS in a single male infant due to bi-allelic mutations in the gene pallidin. The gene product encodes a component of Biogenesis of Lysosome-related Organelles Complex-1, a protein complex responsible for intracellular vesicle formation. Members of the Section also described the clinical and molecular manifestations of HPS in non-Puerto Rican Hispanic individuals and the second family in the world with HPS-8. The Sections pulmonary group reported interstitial lung disease in three HPS-2 patients, documenting this complication as part of the HPS-2 phenotype. Section investigators continue to pursue the etiology of the lung fibrosis of HPS, through studies of surface glycoproteins such as galectin-3 in blood and pulmonary lavage fluid. In collaboration with NIAID investigators, Section scientists are studying mast cell function in HPS, since the basophilic granules of these cells are lysosome-like organelles. The Section also collaborated on a project to demonstrate that KXD1, a blos1 interacting protein, functions in the formation of lysosome-related organelles. 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 published papers describing hepatorenal findings in obligate heterozygotes for ARPKD/CHF and portal hypertension in Autosomal Dominant Polycystic Kidney Disease. 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. In collaborative efforts, they reported the platelet dense body results of CHD patients with and without bone marrow transplantation, and are extensively characterizing the clinical, molecular, and cellular aspects of mild CHD patients with neurological manifestations. In collaboration with NCATS investigators, basic scientists in the Section are pursuing treatment of the neurological symptoms of CHD using small molecule therapy and a mouse model that manifests neurological findings. 6. One Section investigator has established 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. He and his NEI collaborators have shown that nitisinone increases plasma tyrosine levels and improves ocular and skin pigmentation abnormalities in a mouse model of oculocutaneous albinism, paving the way for possible treatment in humans. 7. In miscellaneous collaborative pursuits, Section investigators have provided the GNE gene, defective in Hereditary Inclusion Body Myopathy, to a patient intravenously. Other Section members have reported an unusual patient with Smith-Magenis syndrome and an isolated RAI1 mutation, the different isoforms of UDP-GlcNac 2-epimerase/ManNAc kinase in various tissues, the renal pathology of the Gne mouse, the role of cysteamine in suppressing cancer metastases, and the fact that the lysosomal membrane sialic acid transporter sialin serves as a nitrate transporter in the plasma membrane. 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 6800 inquiries and 2500 sets of 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 530 patients and admitted over 450, providing state-of-the-art clinical investigations in every case, and solving approximately 100 diagnostic dilemmas, some of which are extremely rare disorders. UDP investigators have also identified 20 new diseases associated with genetic variants, and are pursuing demonstration of the basic defects via cellular and biochemical studies. Publications emanating from the UDP include descriptions of a new spastic ataxia-neuropathy syndrome due to homozygous AFG3L2 mutations, a very rare compound heterozygous case of fatty acid hydroxylase deficiency and neurodegeneration, a case of IgG4 sclerosing disease with mastoiditis, a girl with juvenile onset GM1 gangliosidosis, and neurotransmitter deficiency in the CSF of patients with spastic paraplegia and gait abnormalities (SPG11). The UDP has also advanced the field of next generation sequencing analysis by publishing papers that describe whole exome sequencing filters and tools for analyzing variants in small Mendelian pedigrees, lists of false positive variants and of exons that behave well in exome sequencing platforms, variants in genes associated with muscle disease and spastic paraplegia, the use of SNP genotyping in whole exome sequence analysis, and quantification of mosaicism using a cumulative distribution function to analyze SNP arrays. Finally, UDP leaders have written a review and an editorial about the Program in the past year. Recently, Section leaders secured 7 years of support for expansion of the Program to extramural sites.