Human Biochemical Genetics

人类生化遗传学

基本信息

批准号：
10911735
负责人：
William Gahl
金额：
$ 347.88万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/10911735
关键词：
Adult Advocacy African Albinism Alkaptonuria Alleles Artificial Intelligence Authorization documentation Award Bacterial Infections Basic Science Biochemical Biochemical Genetics Biochemical Pathway Biochemistry Biological Biological Sciences Birt-Hogg-Dube Syndrome Bone Diseases CHS1 gene Caring Catabolism Cells Cellular biology Clinical Clinical Protocols Clinical Research Clinical Trials Collaborations Communities Complementary DNA Congenital disorders of glycosylation Cooperative Research and Development Agreement Country Cysteamine Cystinosis Cytoplasmic Granules Defect Developing Countries Diagnosis Disease Doctor of Philosophy Elements Endocannabinoids Enrollment Enzymes Extramural Activities Fibroblasts Food and Drug Administration Drug Approval Fostering Foundations Genes Genetic Genetic Diseases Genetic study Genotype Glean Glycoproteins Goals Hemorrhage Heritability Hermanski-Pudlak Syndrome Histiocytosis Homogentisic Acid Human Immunity Immunologist Impairment Inflammation International Journals Lead Leadership Left Lipids Lung Lung diseases Lymphocyte Lysosomal Storage Diseases Lysosomes Medical Molecular Molecular Disease Mus Mutation Myopathy Myosin ATPase N-acetylmannosamine NOS2A gene National Human Genome Research Institute National Institute of Neurological Disorders and Stroke National Institute on Alcohol Abuse and Alcoholism Natural History Neuhauser syndrome Neurodevelopmental Disorder Neurologic Neurologist Neurology Neuromuscular Diseases Neurons New Drug Approvals Oculocutaneous Albinism Oral Osteogenesis Imperfecta Paper Pathogenicity Patient Care Patients Pharmaceutical Preparations Phenotype Physicians Pituitary Gland Play Principal Investigator Production Prognosis Proteins Proteus Syndrome Protocols documentation Publishing Pulmonary Fibrosis RNA Splicing Rare Diseases Renal glomerular disease Reporting Research Research Personnel Research Project Grants Role STAT4 gene Scientist Services Sialic Acids Smith Magenis syndrome Specimen Study Section Syndrome Time Tubular formation Tyrosine United States National Institutes of Health Variant Vesicle Visual Acuity Work Writing arthropathies authority autoinflammatory diseases base calcification cell motility chediak-higashi syndrome clinical research site doctoral student gain of function gene therapy hexokinase human disease inhibitor insight interest lectures loss of function member molecular diagnostics neglect nephropathic cystinosis neurodevelopment preservation programs randomized placebo controlled study receptor research study safety testing slow potential spasticity symposium translational research program

项目摘要

The Section on Human Biochemical Genetics studies genetic diseases to better understand biochemical pathways and to care for patients with rare and neglected diseases. The Section pursues these goals by investigating, diagnosing, and treating several disorders through clinical protocols managed by world experts. 1. William Gahl, MD, PhD, continued his 42 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Gahl elucidated in 1982. This year, he evaluated several cystinosis patients, consulted on U.S. and international patients, and presented extensively at the Cystinosis Research Networks conference. His collaborative work showing preservation of glomerular and tubular function by early oral cysteamine therapy was published this year, along with elucidation of the role of FGF23 in hyperphosphatemia. Another Section protocol investigates Congenital Disorders of Glycosylation (CDGs, i.e., multisystemic disorders due to impaired synthesis of glycoproteins), with Lynne Wolfe, CRNP, as principal investigator. This year, she and her collaborators described genotype/phenotype correlations in Fryns syndrome due to biallelic mutations in PIGN (a GPI anchor protein) and reported specific lipid elevations in CDGs. Wendy Introne, MD, manages the Sections patients with alkaptonuria, a bone and joint disorder due to accumulation of homogentisic acid (HGA), an intermediate in tyrosine catabolism. She has enrolled >100 patients in her clinical protocol and is pursuing New Drug Approval by the FDA for nitisinone, a drug that we demonstrated lowers HGA production by 95%. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis due to biallelic mutations in the LYST gene. In the past year, Dr. Introne and colleagues pursued the mechanism of neurological impairment in CHD, demonstrating defective autophagic lysosome reformation in CHD neurons. They also advanced CHD molecular diagnostics by using cDNA sequencing and wrote a review on the disease. Dr. Introne has continued the Sections studies of Smith-Magenis syndrome, describing Birt-Hogg-Dube syndrome in a patient. David Adams, MD, PhD, continues to provide the albinism community with expertise and advice, bolstered by the transfer of Stacie Loftus, PhD, to the Section from Dr. Pavans lab. They reported the cause of missing heritability in a large number of oculocutaneous albinism (OCA) type 1B patients. Adams and NEI collaborators also employed artificial intelligence to evaluate visual acuity in patients with foveal hypoplasia. Bernadette Gochuico, MD, a pulmonologist in the Section, and collaborators described structural and functional pulmonary abnormalities in osteogenesis imperfecta and cystic lung disease in Proteus Syndrome. 2. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 11 genetic disorders with OCA and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 have fatal pulmonary fibrosis. Before Dr. Gochuico, left the NIH and transferred her HPS clinical protocol to Dr. Introne, she and colleagues described the Sections pursuit of gene therapy for HPS pulmonary fibrosis and reported increased cell motility in HPS lung fibroblasts due to dysregulated myosin. Dr. Gochuico also collaborated with extramural researchers to elucidate elements of abnormal immunity and inflammation in HPS-1. Other Section members reported a unique, disease-causing deletion in the HPS3 gene and wrote online reviews on HPS for GeneReviews and for the National Organization for Rare Disorders (NORD). Section members continue to work with NIAAA scientists on a dual inhibitor of endocannabinoid receptor 1 and inducible nitric oxide synthase that can potentially slow the progression of HPS pulmonary fibrosis. Members of the Section continue to care for HPS patients in association with the HPS Network. 3. The Section has a longstanding interest in sialic acid disorders. One such disease is GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid synthesis. Francis Rossignol, MD, is principal investigator of a pivotal clinical trial testing the safety and efficacy of the sialic acid precursor, N-acetylmannosamine (ManNAc), for patients with GNE myopathy. This multicenter, randomized, placebo-controlled study is part of NeuroNext, an NINDS consortium of national neurology centers, with CRADA support from Leadiant Biosciences, Inc. In May of 2023, he completed enrollment of the NHGRI contingent of 18 patients. Marjan Huizing, PhD, and other Section members are now preparing a clinical protocol to study ManNAc in renal glomerular diseases. Section members also investigate various aspects of Free Sialic Acid Storage Disorders (FSASD) and have created a consortium of 18 international investigators studying disorders of sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). The consortium meets regularly to coordinate research and includes an Oxford-Cambridge Program PhD student, Marya Sabir. In 2023, Dr. Huizing wrote an online review of FSASD for NORD. 4. Section members lead the NIH Undiagnosed Diseases Program (UDP), the founding member of the Undiagnosed Diseases Network (UDN), a national consortium of 12 clinical sites and supporting cores. The UDP investigates patients with mysterious conditions, making diagnoses and describing new disorders and disease mechanisms. Drs. Gahl and Adams co-direct the UDP and May Malicdan, MD, PhD, manages the UDPs translational research program. This year, she and her colleagues and collaborators discovered a new neurodevelopmental disease due to biallelic mutations in ATG4D and a new disorder of spasticity and neuroregression associated with generalized splicing defects resulting from SNAPC4 loss-of-function variants. Dr. Malicdan also reported a unique, atypical presentation of a tubulinopathy due to a TUBB4B mutation. Camilo Toro, MD, is the master neurologist who directs the adult portion of the UDP. This year, he collaborated with Section, IRP, and extramural investigators to describe the molecular basis of ROSAH syndrome (gain-of-function ALPK1 variants), publish a broad characterization of African Nodding Syndrome, report a de novo HK1 (hexokinase 1) variant as a cause of Boucher-Neuhauser syndrome, describe a myopathy due to a splice variant in MYH2, write an article on pituitary hypersecretion due to-loss of-function PAM variants, and summarize the genetic bases of UDP patients with intracerebral calcifications. Section and UDP investigators collaborated with immunologists to describe a new autoinflammatory disease due to pathogenic variants in STAT4. Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment. 5. For the international rare disease community, Dr. Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of >130 physicians and scientists from >40 nations; with the Wilhelm Foundation (a rare and undiagnosed diseases advocacy group), he established the UDNI in 2014. In 2022, Gahl coordinated the 11th UDNI conference in Vienna, established a Champions Initiative to foster UDPs in developing nations, and published papers on the value of clinical networks for rare diseases and the unmet needs of undiagnosed patients in various countries. With colleagues, he wrote articles on the UDN, insights gleaned from the UDP, and the relationship between the UDNI and a new journal entitled Rare. Gahl also delivered 7 invited national and international talks, including the Roscoe Brady Award lecture for WORLDSymposium.

人类生化遗传学科研究遗传疾病，以更好地了解生化途径并照顾患有罕见和被忽视疾病的患者。该科通过世界专家管理的临床方案调查、诊断和治疗多种疾病来实现这些目标。 1. William Gahl，医学博士、哲学博士，继续为肾病性胱氨酸病患者提供 42 年的服务，这是一种溶酶体贮积病，Gahl 于 1982 年阐明了其基本缺陷。今年，他评估了几名胱氨酸病患者，为美国和国际患者提供咨询，并在胱氨酸病研究网络会议上进行了广泛的介绍。他的合作工作于今年发表，展示了通过早期口服半胱胺疗法保留肾小球和肾小管功能，并阐明了 FGF23 在高磷血症中的作用。另一个部分的方案研究先天性糖基化疾病（CDG，即由于糖蛋白合成受损而导致的多系统疾病），由 CRNP 的林恩·沃尔夫 (Lynne Wolfe) 担任首席研究员。今年，她和她的合作者描述了由于 PIGN（一种 GPI 锚蛋白）双等位基因突变导致的 Fryns 综合征的基因型/表型相关性，并报告了 CDG 中的特定脂质升高。 Wendy Introne 医学博士负责治疗黑酸尿症患者，黑酸尿症是一种由于尿黑酸 (HGA)（酪氨酸分解代谢的中间体）积聚而导致的骨和关节疾病。她已在其临床方案中招募了超过 100 名患者，并正在寻求 FDA 批准尼替西农新药，我们证明该药物可将 HGA 产量降低 95%。 Introne 博士还是 Chediak-Higashi 病 (CHD) 方面的国际权威，CHD 是一种由 LYST 基因双等位基因突变引起的巨大细胞内颗粒、致命细菌感染和淋巴细胞组织细胞增多症的疾病。在过去的一年里，Introne 博士及其同事研究了 CHD 神经损伤的机制，证明了 CHD 神经元中存在缺陷的自噬溶酶体重组。他们还通过使用 cDNA 测序推进了 CHD 分子诊断，并撰写了有关该疾病的评论。 Introne 博士继续进行 Smith-Magenis 综合征的切片研究，描述了一名患者的 Birt-Hogg-Dube 综合征。 David Adams 医学博士、哲学博士在 Stacie Loftus 博士从 Pavans 博士实验室调到该科的支持下，继续为白化病界提供专业知识和建议。他们报告了大量眼皮肤白化病 (OCA) 1B 型患者遗传性缺失的原因。 Adams 和 NEI 的合作者还利用人工智能来评估黄斑中心凹发育不全患者的视力。该科的肺科医生 Bernadette Gochuico 医学博士及其合作者描述了变形杆菌综合征中成骨不全和囊性肺疾病中的肺部结构和功能异常。 2. 该科还研究 Hermansky-Pudlak 综合征 (HPS)，该综合征由 11 种遗传性疾病组成，伴有 OCA 和由于细胞内囊泡形成异常而导致的出血。 1、2 和 4 型具有致命性肺纤维化。在 Gochuico 博士离开 NIH 并将她的 HPS 临床方案转让给 Introne 博士之前，她和同事描述了该部门对 HPS 肺纤维化基因治疗的追求，并报告了由于肌球蛋白失调而导致 HPS 肺成纤维细胞的细胞运动性增加。 Gochuico 博士还与校外研究人员合作，阐明了 HPS-1 中异常免疫和炎症的因素。其他部门成员报告了 HPS3 基因中独特的致病缺失，并为 GeneReviews 和国家罕见疾病组织 (NORD) 撰写了 HPS 在线评论。该部门成员继续与 NIAAA 科学家合作开发内源性大麻素受体 1 和诱导型一氧化氮合酶的双重抑制剂，该抑制剂可能会减缓 HPS 肺纤维化的进展。该科的成员继续与 HPS 网络合作护理 HPS 患者。 3. 该科对唾液酸疾病有着长期的兴趣。其中一种疾病是 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 编码唾液酸合成的限速酶。 Francis Rossignol 医学博士是一项关键临床试验的首席研究员，该试验测试唾液酸前体 N-乙酰甘露糖胺 (ManNAc) 对 GNE 肌病患者的安全性和有效性。这项多中心、随机、安慰剂对照研究是 NeuroNext（一个由国家神经病学中心组成的 NINDS 联盟）的一部分，并得到了 Leadiant Biosciences, Inc. 的 CRADA 支持。2023 年 5 月，他完成了 NHGRI 18 名患者的入组。 Marjan Huizing 博士和其他部门成员目前正在准备研究 ManNAc 在肾小球疾病中的临床方案。该部门成员还研究游离唾液酸储存障碍 (FSASD) 的各个方面，并在倡导团体 STAR（萨拉治疗和研究）的支持下创建了一个由 18 名国际研究人员组成的联盟，研究溶酶体唾液酸排出障碍。该联盟定期召开会议以协调研究，其中包括牛津-剑桥项目的博士生玛丽亚·萨比尔 (Marya Sabir)。 2023 年，Huizing 博士为 NORD 撰写了一篇关于 FSSD 的在线评论。 4. 科室成员领导 NIH 未确诊疾病计划 (UDP)，是未确诊疾病网络 (UDN) 的创始成员，该网络是一个由 12 个临床中心和支持核心组成的国家联盟。 UDP 调查患有神秘病症的患者，进行诊断并描述新的疾病和疾病机制。博士。 Gahl 和 Adams 共同领导 UDP，May Malicdan 博士负责管理 UDP 转化研究项目。今年，她和她的同事及合作者发现了一种由 ATG4D 双等位基因突变引起的新神经发育疾病，以及一种与 SNAPC4 功能丧失变异引起的全身剪接缺陷相关的新痉挛和神经退行性疾病。 Malicdan 博士还报告了由 TUBB4B 突变引起的微管蛋白病的独特、非典型表现。卡米洛·托罗 (Camilo Toro) 医学博士是神经科医生，负责指导 UDP 的成人部分。今年，他与部门、IRP 和校外研究人员合作，描述了 ROSAH 综合征（功能获得性 ALPK1 变异体）的分子基础，发表了非洲点头综合征的广泛特征，报告了新的 HK1（己糖激酶 1）变异体作为 Boucher-Neuhauser 综合征的原因，描述由于 MYH2 剪接变异引起的肌病，撰写一篇关于垂体分泌过多的文章至功能丧失的 PAM 变异，并总结 UDP 脑内钙化患者的遗传基础。 Section 和 UDP 研究人员与免疫学家合作，描述了一种由 STAT4 致病变异引起的新的自身炎症性疾病。其他组成员报告了 KMT5B 单倍体不足损害小鼠和人类神经发育的机制。 5. 对于国际罕见病界，Gahl 博士领导着国际未确诊疾病网络 (UDNI)，该联盟由来自 40 多个国家的 130 多名医生和科学家组成； 2014 年，他与 Wilhelm 基金会（一个罕见和未确诊疾病倡导组织）共同建立了 UDNI。2022 年，Gahl 协调了在维也纳举行的第 11 届 UDNI 会议，制定了一项倡导者倡议，以促进发展中国家的 UDP，并发表了有关价值的论文罕见疾病的临床网络以及各国未确诊患者未得到满足的需求。他与同事一起撰写了有关 UDN 的文章、从 UDP 收集的见解以及 UDNI 与名为 Rare 的新期刊之间的关系。加尔还受邀发表了 7 场国内和国际演讲，包括 WORLD Symposium 的罗斯科·布雷迪奖演讲。

项目成果

期刊论文数量（142）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.

DOI：
10.1093/hmg/ddaa237
发表时间：
2021-01-06
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Nistala H;Dronzek J;Gonzaga-Jauregui C;Chim SM;Rajamani S;Nuwayhid S;Delgado D;Burke E;Karaca E;Franklin MC;Sarangapani P;Podgorski M;Tang Y;Dominguez MG;Withers M;Deckelbaum RA;Scheonherr CJ;Gahl WA;Malicdan MC;Zambrowicz B;Gale NW;Gibbs RA;Chung WK;Lupski JR;Economides AN
通讯作者：
Economides AN

Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients.

DOI：
10.1016/j.ymgme.2017.05.017
发表时间：
2017-08
期刊：
Molecular genetics and metabolism
影响因子：
3.8
作者：
Brofferio A;Sachdev V;Hannoush H;Marshall JD;Naggert JK;Sidenko S;Noreuil A;Sirajuddin A;Bryant J;Han JC;Arai AE;Gahl WA;Gunay-Aygun M
通讯作者：
Gunay-Aygun M

An Integrative Multiomics Framework for Identification of Therapeutic Targets in Pulmonary Fibrosis.

DOI：
10.1002/advs.202207454
发表时间：
2023-06
期刊：
ADVANCED SCIENCE
影响因子：
15.1
作者：
Arif, Muhammad;Basu, Abhishek;Wolf, Kaelin M.;Park, Joshua K.;Pommerolle, Lenny;Behee, Madeline;Gochuico, Bernadette R.;Cinar, Resat
通讯作者：
Cinar, Resat

Progressive pulmonary fibrosis in a murine model of Hermansky-Pudlak syndrome.