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.

人类生物化学遗传学研究部分的新陈代谢和其他遗传疾病的出生错误，以深入了解细胞机制，并照顾被忽视的罕见病患者。本节以各种方式追求这些目标。 1。专家研究，诊断和治疗许多特定疾病。在过去的一年中，该部分继续为肾病性囊肿性服务40年，向全世界的患者，医师和倡导组织提供咨询。 Gahl博士帮助制定了有关囊肿骨病管理的国际共识声明，并为FGF23在调节骨矿化中的作用中的作用有了新的见解。他还合作了在德国举办的世界上首次新生儿囊肿性筛查计划。 Wendy博士的固有照料对烷酸核酸烷酸（由于均匀酸的积累引起的结缔组织疾病）的患者提供了照顾，描述了主动脉膨胀性和甲状腺功能受损。 Internos博士还是Chediak-Higashi病（CHD）的国际权威，一种巨大细胞内颗粒，致命的细菌感染和淋巴细胞性组织细胞增多症的疾病。她描述了CHD的神经心理学方面，写了一份确定的评论，并为创建4个CHD诱导的多能干细胞系做出了贡献。大卫·亚当斯（David Adams）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。特殊志愿者和前部成员Juvi Estrada Veras博士报道了一种称为Erdheim-Chester病的罕见组织细胞增多症的神经，口服，甲状腺和肾上腺表现。特殊志愿者Meral Gunay-Aygun博士分析了过去十年来作为该部分成员收集的Ciliopathy数据。纤毛病，细胞上纤毛的疾病包括乔伯特综合征（JS），阿尔斯特罗姆综合征和多囊性肾脏疾病。 Gunay博士及其同事使用小鼠模型发现了JS（Barttin）的遗传修饰剂，并使用外显子跳过营救了JS细胞的纤毛蛋白缺损。他们描述了纤毛病的特定器官特定表现形式，写了有关阿尔斯特罗姆综合症的权威评论，并为JS提供了管理建议。现任医师科学家发展计划的Carlos Ferreira博士启动了一项临床方案，研究了该酶缺乏症患者的ENPP1酶替代疗法；相关的疾病包括婴儿期的普遍动脉钙化（通常在新生儿时期致命）和常染色体隐性肾上腺磷酸性rickept 2. 2。借助该部分参与CDG财团，其与NIH未诊断的疾病计划（UDP）的密切相互作用以及PNP Lynne Wolfe的兴趣，部分成员与SLC25A2中的30例患者进行了合作，该患者在SLC25A2中的突变患者，该患者编码了UDP-Galactose s audpp-galactose sombasterters。对于NIAID科学家，他们报道了X连锁免疫缺陷的糖基化缺陷，由于MAGT1突变而引起的镁缺陷（XMEN）疾病，这是一种合成活化的Glycan前体的镁转运蛋白。其他CDG是由磷脂酰肌醇聚糖的缺陷导致的，后者形成GPI在细胞表面锚固。部分成员合作报告了患有PIGM毒素突变和神经系统发现的患者，由于ARV1突变引起的GPI锚定缺乏以及40例PIGA突变患者。林恩·沃尔夫（Lynne Wolfe）帮助描述了患有碳脂糖质合成酶2缺乏症的个体，他们可能会从尿苷补充中受益，而卡洛斯·费雷拉（Carlos Ferreira）博士描述了索尔 - 威尔逊综合征的临床特征，其糖蛋白缺陷是由于cogi cogy comporty comporty comportion comportion comportion compontion comportial oilig a compontion comportial nevernal netail compontion comportial newsements compontion compontion comportial nevential sys saul-wilson综合征缺陷。 3。本节还研究了Hermansky-Pudlak综合征（HPS），该综合征由10个罕见的眼皮白化病的罕见遗传疾病和由于细胞内囊泡的异常形成而导致的出血。 1、2和4型具有致命的肺纤维化。 Bernadette Gochuico博士领导了与NIAAA和NCAT的合作，研究了一个分子，该分子结合了对诱导型一氧化氮合酶和内源性大麻素受体CB1的拮抗作用，以治疗HPS肺纤维化。使用May Malicdan博士开发的小鼠模型，部分合作者表明，诱导纤维化的药物博来霉素还会引起肺部细胞的药物外排。 Marjan Huizing博士与May Malicdan一起对引起HP的突变进行了评论，临床医生向全世界的HPS医师，患者和倡导组织提供了建议。 4。Drs。 Huizing和Nuria Carrillo与合作者开发了一种LC-MS/MS方法，用于测量人类白细胞中的胞苷-5-单磷-N-乙酰神经氨酸，并证明由于人类肾脏功能降低而导致血浆唾液酸水平升高。 Huizing和Section研究人员建立了一个工作组，以研究Salla病，这是一种在倡导组Star（Salla治疗和研究）的支持的情况下，是一种从溶酶体中出现有缺陷的游离唾液酸出口疾病。本节的主要推力涉及刺激肌病，这是由于gne中双重突变引起的晚发神经肌肉疾病，该疾病编码唾液酸生物合成中的速率限制酶。 Carrillo博士在全国范围内神经疾病的一部分，开始了唾液酸前体的多中心，随机的，安慰剂对照的临床试验，N-乙酰男性诺胺（MANNAC）。该试验得到了Leadiant Biosciences，Inc。的Crada支持，并将于2020年秋天开始。今年，Huizing博士描述了在肾肾小球疾病中使用MANNAC的理由。 5。本节的成员还领导NIH UDP，这是NIH普通基金支持的未诊断疾病网络（UDN）的一部分。 UDN是一种精确医学的模型，致力于诊断有神秘状况的患者并发现新的疾病和疾病机制。 Gahl博士坐在UDN工作组，Adams博士联合主席UDN指导委员会是一个由12个临床场所组成的国家财团和支持核心的国家财团。在过去的一年中，本节帮助UDP开发了强大的序列分析管道，增强了针对颅面和口服表型的本体论词汇，记录了UDN对生物医学科学的独特贡献，使用机器学习确定临床术语，并使用机器学习，并描述稀有未诊断疾病的新诊断方法。国际贡献包括非洲罕见疾病的行动呼吁，对罕见疾病调查的开放科学辩护，以及UDP于2014年建立的未诊断的未诊断疾病国际疾病网络国际（UDNI）的五年后续。 Malicdan博士率先在UDP患者的部分中进行了转化研究。她和她的同事和合作者描述了由于YPEL3，肾脏和颅面异常的突变，与适配器蛋白PHETA1/2缺乏相关的肾脏和颅面异常以及由于SLC12A2的删除而引起的综合性听力损失。其他部分的研究者已经发布了由于HNF1B的删除，由于登革热病毒而导致的慢性气球炎，由于ARH3突变引起的发育障碍，非典型Waardenburg综合征引起的慢性脑脑炎，非典型SOX10引起的，由于新型SOX10突变，与kmt2b的临床特征以及kmt2b-lidoder nistry and Cognation Cognity的临床特征，以及一种极为异常的变化。神经病。