Human Biochemical Genetics

人类生化遗传学

• 批准号: 10267091
• 负责人: William Gahl
• 金额: $ 498.75万
• 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/10267091
• 关键词: Adaptor Signaling Protein; Adrenal Glands; Advocacy; Africa; Albinism; Alkaptonuria; Alstrom syndrome; Anabolism; Bacterial Infections; Basic Science; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biological Sciences; Bleomycin; Bone Diseases; CNR1 gene; Caring; Cell Line; Cell surface; Cells; Cellular biology; Characteristics; Chronic; Cilia; Clinical; Clinical Protocols; Clinical Research; Collaborations; Communities; Congenital disorders of glycosylation; Connective Tissue Diseases; Consensus; Consultations; Cooperative Research and Development Agreement; Country; Craniofacial Abnormalities; Cystinosis; Cytidine; Cytoplasmic Granules; Data; Defect; Dengue Virus; Development; Diagnosis; Disease; Disease Pathway; Drug Efflux; Endocannabinoids; Enzymes; Erdheim-Chester Disease; Face; Familial hypophosphatemic bone disease; Fibrosis; Finnish Type Sialic Acid Storage Disease; Funding; Galactose; Genetic; Genetic Diseases; Genetic study; Germany; Glycoproteins; Goals; Golgi Apparatus; Hemorrhage; Hermanski-Pudlak Syndrome; Histiocytosis; Homogentisic Acid; Human; Hypomagnesemia; Immunologic Deficiency Syndromes; Impairment; Inborn Errors of Metabolism; Individual; International; Investigation; Joubert syndrome; Kidney; Lead; Leukocytes; Ligase; Link; Lung; Lymphocyte; Lysosomes; Machine Learning; Magnesium; Measures; Medical; Methods; Mission; Modeling; Molecular; Morphology; Motor; Mutation; Myopathy; N-Acetylneuraminic Acid; N-acetylmannosamine; NOS2A gene; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism; Natural History; Neonatal Screening; Netherlands; Neurologic; Neurological observations; Neurology; Neuromuscular Diseases; Neuropathy; Neuropsychology; Oculocutaneous Albinism; Ontology; Oral; Organ; Other Genetics; PI-Glycan; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Physiologic calcification; Plasma; Polycystic Kidney Diseases; Polysaccharides; Program Development; Protein Glycosylation; Proteins; Protomer; Publishing; Pulmonary Fibrosis; Rare Diseases; Recommendation; Regulation; Renal function; Renal glomerular disease; Reporting; Research; Research Personnel; Research Project Grants; Role; Science; Scientist; Sensory; Sequence Analysis; Services; Sialic Acids; Specimen; Study Section; Supplementation; Syndrome; Thyroid Function Tests; Thyroid Gland; Time; Translational Research; United States National Institutes of Health; Uridine; Variant; Vesicle; Vocabulary; Waardenburg syndrome; analysis pipeline; arterial calcification of infancy; authority; base; chediak-higashi syndrome; ciliopathy; clinical research site; cognitive change; craniofacial; developmental disease; enzyme deficiency; enzyme replacement therapy; exon skipping; falls; follow-up; glycosylation; hearing impairment; induced pluripotent stem cell; insight; interest; meetings; member; mouse model; neglect; neonatal period; nephropathic cystinosis; novel; novel diagnostics; open data; patient advocacy group; precision medicine; programs; randomized placebo-controlled clinical trial; rare genetic disorder; research study; screening program; support network; treatment research; volunteer; working group

The Section on Human Biochemical Genetics studies inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected rare disease patients. The Section pursues these goals in various ways. 1. Section experts investigate, diagnose, and treat many specific disorders. In the past year, the Section continued its 40 years of service to nephropathic cystinosis, providing consultations to patients, physicians, and advocacy groups throughout the world. Dr. Gahl helped formulate an international consensus statement on the management of cystinotic bone disease and contributed to new insights into the role of FGF23 in the regulation of bone mineralization in cystinosis. He also collaborated on the first newborn screening program for cystinosis in the world, conducted in Germany. Dr. Wendy Introne cared for patients with alkaptonuria (a connective tissue disorder due to accumulation of homogentisic acid), describing impaired aortic distensibility and thyroid function. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis. She described the neuropsychological aspects of CHD, wrote a definitive review, and contributed to the creation of 4 CHD induced pluripotent stem cell lines. Dr. David Adams continued to serve the albinism community by providing expertise, advice, and collaborations. Dr. Juvi Estrada Veras, a Special Volunteer and former Section member, reported the neurological, oral, thyroid, and adrenal manifestations of a rare histiocytosis called Erdheim-Chester Disease. Dr. Meral Gunay-Aygun, a Special Volunteer, analyzed ciliopathy data that she had collected over the past decade as a member of the Section. Ciliopathies, disorders of immotile cilia on cells, include Joubert Syndrome (JS), Alstrom syndrome, and polycystic kidney diseases. Dr. Gunay and colleagues discovered a genetic modifier of JS (barttin) using a mouse model and rescued the ciliary protein defect of JS cells using exon skipping. They described the organ-specific manifestations of ciliopathies, wrote the definitive review on Alstrom Syndrome, and provided management recommendations for JS. Dr. Carlos Ferreira, now in the Physician Scientist Development Program, initiated a clinical protocol to study ENPP1 enzyme replacement therapy in individuals with deficiency of that enzyme; the associated disorders include Generalized Arterial Calcification of Infancy (often fatal in the neonatal period) and Autosomal Recessive Hypophosphatemic Rickets type 2. 2. Congenital Disorders of Glycosylation (CDGs) are biochemical defects that result in abnormal glycosylation of proteins. By virtue of the Sections involvement in a CDG Consortium, its close interactions with the NIH Undiagnosed Diseases Program (UDP), and the interest of Lynne Wolfe, PNP, Section members have collaborated to describe 30 patients with mutations in SLC25A2, which encodes a UDP-galactose transporter. With NIAID scientists, they reported glycosylation defects in X-linked Immunodeficiency with Magnesium Defect (XMEN) disease due to mutations in MAGT1, a magnesium transporter required for enzymes that synthesize activated glycan precursors. Other CDGs result from defects in phosphatidylinositol glycans, which form GPI anchors on the surface of cells. Section members collaborated to report patients with a PIGM protomer mutation and neurological findings, GPI anchor deficiency due to ARV1 mutations, and 40 patients with PIGA mutations. Lynne Wolfe helped describe individuals with carbomoylphosphate synthetase 2 deficiency who may benefit from supplementation with uridine and Dr. Carlos Ferreira described the clinical characteristics of Saul-Wilson Syndrome, whose glycoprotein defects result from morphological abnormalities in the Golgi network due to mutations in COG4 (Component of Oligomeric Golgi Complex 4). 3. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 10 rare genetic disorders of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 have fatal pulmonary fibrosis. Dr. Bernadette Gochuico leads a collaboration with NIAAA and NCATS investigating a molecule that combines inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 to treat HPS pulmonary fibrosis. Using mouse models developed by Dr. May Malicdan, Section collaborators demonstrated that the fibrosis-inducing drug bleomycin also causes drug efflux from lung cells. Dr. Marjan Huizing, along with May Malicdan, wrote reviews on the mutations causing HPS, and Section clinicians provided advice to HPS physicians, patients and advocacy groups throughout the world. 4. Drs. Huizing and Nuria Carrillo, with collaborators, developed an LC-MS/MS method to measure cytidine-5-monophospho-N-acetylneuraminic acid in human leukocytes and demonstrated increased plasma sialic acid levels due to reduced kidney function in humans. Huizing and Section investigators established a working group to study Salla Disease, a disorder of defective free sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). A major thrust of the Section involves GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Dr. Carrillo initiated a multicenter, randomized, placebo-controlled clinical trial of the sialic acid precursor, N-acetylmannosamine (ManNAc) in GNE myopathy as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial has CRADA support from Leadiant Biosciences, Inc., and will start in the fall of 2020. This year, Dr. Huizing described the rationale for using ManNAc in renal glomerular diseases. 5. Members of the Section also lead the NIH UDP, which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. The UDN, a model for Precision Medicine, strives to diagnose patients with mysterious conditions and to discover new disorders and disease mechanisms. Dr. Gahl sits on the UDN Working Group and Dr. Adams co-chairs the Steering Committee of the UDN, a national consortium of 12 clinical sites and supporting cores. In the past year, the Section has helped the UDP develop a powerful sequence analysis pipeline, enhance ontological vocabularies for craniofacial and oral phenotypes, document the unique contributions of the UDN to the biomedical sciences, identify clinical terms using machine learning, and describe new diagnostic approaches to rare undiagnosed diseases. International contributions included a call to action for rare diseases in Africa, a plea for open science in the investigation of rare diseases, and the 5-year follow-up on the Undiagnosed Diseases Network International (UDNI), established by the UDP in 2014. In 2020, Section members organized the 8th international UDNI meeting in Nijmegen, the Netherlands. Dr. Malicdan has spearheaded the translational research performed within the Section on UDP patients. She and her colleagues and collaborators have described a developmental disorder due to mutations in ypel3, renal and craniofacial abnormalities associated with deficiency of the adaptor protein PHETA1/2, and syndromic hearing loss due to deletion of SLC12A2. Other Section investigators have published cases of hypomagnesemia due to deletion of HNF1B, chronic panencephalitis due to dengue virus, developmental impairment due to ARH3 mutations, atypical Waardenburg syndrome due to a novel SOX10 mutation, clinical characteristics of KMT2B-related disorders, and cognitive change related to an extremely rare disorder called Facial Onset Sensory and Motor Neuropathy.

人类生化遗传学部分研究先天性代谢缺陷和其他遗传性疾病，以深入了解细胞机制并照顾被忽视的罕见疾病患者。该科以各种方式实现这些目标。 1. 科室专家调查、诊断和治疗许多特定疾病。去年，该科继续其 40 年来为肾病性胱氨酸病提供的服务，为世界各地的患者、医生和倡导团体提供咨询。 Gahl 博士帮助制定了关于胱氨酸病骨病治疗的国际共识声明，并为 FGF23 在胱氨酸病骨矿化调节中的作用提供了新的见解。他还参与了在德国进行的世界上第一个新生儿胱氨酸病筛查项目。 Wendy Introne 医生负责治疗尿黑酸尿症（尿黑酸积聚导致的结缔组织疾病）患者，描述了主动脉扩张性和甲状腺功能受损的情况。 Introne 博士还是 Chediak-Higashi 病 (CHD) 方面的国际权威，CHD 是一种由巨大细胞内颗粒、致命细菌感染和淋巴细胞组织细胞增多症引起的疾病。她描述了 CHD 的神经心理学方面，撰写了一篇权威评论，并促成了 4 个 CHD 诱导多能干细胞系的创建。大卫·亚当斯博士继续通过提供专业知识、建议和合作来为白化病社区服务。特殊志愿者、前科员 Juvi Estrada Veras 博士报告了一种称为埃尔德海姆-切斯特病的罕见组织细胞增多症的神经、口腔、甲状腺和肾上腺表现。特殊志愿者 Meral Gunay-Aygun 博士分析了她在过去十年作为该科成员收集的纤毛病数据。纤毛病，即细胞上纤毛不动的疾病，包括朱伯特综合征 (JS)、阿尔斯特罗姆综合征和多囊肾病。 Gunay 博士及其同事利用小鼠模型发现了 JS (barttin) 的基因修饰剂，并利用外显子跳跃修复了 JS 细胞的纤毛蛋白缺陷。他们描述了纤毛病的器官特异性表现，撰写了关于阿尔斯特罗姆综合征的权威评论，并为 JS 提供了治疗建议。 Carlos Ferreira 博士目前在医师科学家发展计划中，发起了一项临床方案，研究针对缺乏 ENPP1 酶的个体的 ENPP1 酶替代疗法；相关疾病包括婴儿期全身动脉钙化（在新生儿期通常致命）和常染色体隐性遗传性低磷血症性佝偻病 2 型。 2. 先天性糖基化障碍 (CDG) 是导致蛋白质糖基化异常的生化缺陷。凭借该部门参与 CDG 联盟、与 NIH 未诊断疾病计划 (UDP) 的密切互动以及 PNP Lynne Wolfe 的兴趣，该部门成员合作描述了 30 名 SLC25A2 突变患者，该基因编码 UDP -半乳糖转运蛋白。他们与 NIAID 的科学家合作，报告了由于 MAGT1 突变导致 X 连锁免疫缺陷伴镁缺陷 (XMEN) 疾病的糖基化缺陷，MAGT1 是合成活化聚糖前体的酶所需的镁转运蛋白。其他 CDG 是由磷脂酰肌醇聚糖缺陷引起的，磷脂酰肌醇聚糖在细胞表面形成 GPI 锚。该部门成员合作报告了 PIGM 原体突变和神经系统检查结果、ARV1 突变导致的 GPI 锚缺陷的患者，以及 40 名 PIGA 突变的患者。 Lynne Wolfe 帮助描述了碳酰磷酸合成酶 2 缺乏症患者可能会受益于补充尿苷的个体，Carlos Ferreira 博士描述了 Saul-Wilson 综合征的临床特征，该综合征的糖蛋白缺陷是由于 COG4（成分）突变导致高尔基体网络形态异常所致。低聚高尔基体复合体 4)。 3. 该科还研究赫曼斯基-普德拉克综合征 (HPS)，该综合征由 10 种罕见的遗传性疾病组成，包括眼皮肤白化病和细胞内囊泡异常形成引起的出血。 1、2 和 4 型具有致命性肺纤维化。 Bernadette Gochuico 博士领导与 NIAAA 和 NCATS 的合作，研究一种结合诱导型一氧化氮合酶抑制和内源性大麻素受体 CB1 拮抗作用的分子，以治疗 HPS 肺纤维化。使用 May Malicdan 博士开发的小鼠模型，该部门的合作者证明，纤维化诱导药物博来霉素也会导致药物从肺细胞流出。 Marjan Huizing 博士与 May Malicdan 一起撰写了有关导致 HPS 的突变的评论，该部门的临床医生向世界各地的 HPS 医生、患者和倡导团体提供了建议。 4. 博士。 Huizing 和 Nuria Carrillo 与合作者开发了一种 LC-MS/MS 方法来测量人类白细胞中的胞苷-5-单磷酸-N-乙酰神经氨酸，并证明由于人类肾功能下降而导致血浆唾液酸水平升高。 Huizing 和Section 的研究人员在倡导组织STAR（Salla Treatment And Research）的支持下成立了一个工作组来研究Salla 病，这是一种溶酶体游离唾液酸排出缺陷的疾病。该部分的主要内容涉及 GNE 肌病，这是一种由 GNE 的双等位基因突变引起的迟发性神经肌肉疾病，GNE 编码唾液酸生物合成中的限速酶。作为全国神经病学中心 NINDS 联盟 NeuroNext 的一部分，Carrillo 博士发起了一项针对唾液酸前体 N-乙酰甘露糖胺 (ManNAc) 治疗 GNE 肌病的多中心、随机、安慰剂对照临床试验。该试验得到了 Leadiant Biosciences, Inc. 的 CRADA 支持，将于 2020 年秋季开始。今年，Huizing 博士描述了使用 ManNAc 治疗肾小球疾病的基本原理。 5. 该部门的成员还领导 NIH UDP，该网络是 NIH 共同基金支持的未确诊疾病网络 (UDN) 的一部分。 UDN 是精准医学的典范，致力于诊断患有神秘疾病的患者并发现新的疾病和疾病机制。 Gahl 博士是 UDN 工作组成员，Adams 博士是 UDN 指导委员会的联合主席，UDN 是一个由 12 个临床中心和支持核心组成的全国性联盟。在过去的一年中，该科帮助 UDP 开发了强大的序列分析流程，增强了颅面和口腔表型的本体词汇表，记录了 UDN 对生物医学的独特贡献，使用机器学习识别临床术语，并描述了新的诊断罕见未确诊疾病的治疗方法。国际贡献包括呼吁对非洲的罕见疾病采取行动、呼吁在罕见疾病调查中开放科学，以及对 UDP 于 2014 年建立的国际未确诊疾病网络 (UDNI) 进行 5 年后续行动。 2020年，分会成员在荷兰奈梅亨组织了第八届国际UDNI会议。 Malicdan 博士带头在 UDP 患者科内开展转化研究。她和她的同事及合作者描述了由于 ypel3 突变导致的发育障碍、与接头蛋白 PHETA1/2 缺陷相关的肾脏和颅面异常以及由于 SLC12A2 缺失导致的综合征性听力损失。其他部门的研究人员发表了因 HNF1B 缺失导致的低镁血症、因登革热病毒引起的慢性全脑炎、因 ARH3 突变引起的发育障碍、因新的 SOX10 突变引起的非典型 Waardenburg 综合征、KMT2B 相关疾病的临床特征以及与认知改变相关的病例。一种极其罕见的疾病，称为面部感觉和运动神经病。