Human Biochemical Genetics

人类生化遗传学

• 批准号: 10020060
• 负责人: William Gahl
• 金额: $ 486.12万
• 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/10020060
• 关键词: Acidity; Address; Advocacy; Albinism; Alkaptonuria; Alstrom syndrome; American; Anabolism; Animal Model; Apoenzymes; Ataxia; Bacterial Infections; Basic Science; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biological Sciences; Bleomycin; Blood Vessels; CNR1 gene; Caring; Case Study; Cells; Cellular biology; Child; Chinese People; Chlorides; Cilia; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Coloboma; Congenital Heart Defects; Congenital cerebellar hypoplasia; Congenital disorders of glycosylation; Connective Tissue Diseases; Cooperative Research and Development Agreement; Cornea; Country; Cysteine-tRNA ligase; Cytoplasmic Granules; Data; Defect; Dental; Developmental Delay Disorders; Diagnosis; Disease; Disease Pathway; Disease Progression; Dysarthria; Endocannabinoids; Enzymes; Epilepsy; Erdheim-Chester Disease; Face; Family; Fostering; Functional disorder; Funding; Genes; Genetic; Genetic Diseases; Genetic study; Goals; Golgi Apparatus; Hair; Hemorrhage; Hermanski-Pudlak Syndrome; Histiocytosis; Homogentisic Acid; Human; Human Genetics; Inborn Errors of Metabolism; Individual; International; Investigation; Iron; Joubert syndrome; Journals; Knowledge; Lamin B1; Lead; Liver; Lung; Lung diseases; Lymphocyte; Lysosomes; Measures; Medical; Medical Records; Medicine; Melanins; Menkes Kinky Hair Syndrome; Metals; Microcephaly; Mission; Modeling; Molecular; Monophenol Monooxygenase; Motor; Multiprotein Complexes; Mutation; Myopathy; N-acetylmannosamine; NOS2A gene; Nail plate; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism; Natural History; Neurodevelopmental Disorder; Neurology; Neuromuscular Diseases; Neuronal Ceroid-Lipofuscinosis; New England; Oculocutaneous Albinism; Organ; Organelles; Other Genetics; Pathologic; Patient Care; Patients; Pediatrics; Phase; Phenotype; Physicians; Pigments; Polycystic Kidney Diseases; Principal Investigator; Program Reviews; Proteins; Protons; Pseudoxanthoma Elasticum; Publishing; Pulmonary Fibrosis; Rare Diseases; Renal glomerular disease; Reporting; Research; Research Personnel; Research Project Grants; Safety; Sequence Analysis; Sialic Acids; Specimen; Statistical Methods; Stenosis; Study Section; Syndrome; Textbooks; Time; Tyrosine; Uniparental Disomy; United States National Institutes of Health; Variant; Vascular Diseases; Vesicle; WD Repeat; authority; base; biobank; biomedical referral center; bone; boys; calcification; chediak-higashi syndrome; ciliopathy; clinical research site; developmental disease; epileptic encephalopathies; gain of function mutation; genetic disorder diagnosis; hypocupremia; infancy; inhibitor/antagonist; insight; leukodystrophy; meetings; member; metabolomics; mouse model; neglect; nephropathic cystinosis; novel; oxidation; precision medicine; proband; programs; randomized placebo controlled trial; rare genetic disorder; research study; sensory neuropathy; support network; symposium; trafficking; urinary; working group

The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected rare disease patients. Members of the Section have expertise in several specific disorders. 1. In the past year, the Section evaluated 35 nephropathic cystinosis patients, addressed international meetings of investigators and advocacy groups, responded to inquiries from throughout the world, and described the bone abnormalities of the disease. The Section also cared for patients with alkaptonuria (a connective tissue disorder due to accumulation of homogentisic acid) and Chediak-Higashi disease (a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis). One Section investigator, an international authority on albinism, reported increased melanin pigment in albinotic individuals with low tyrosinase activity treated with nitisinone, an inhibitor of tyrosine degradation. Other Section members reported the pulmonary complications and dental manifestations of a rare histiocytosis, Erdheim-Chester Disease. The Section continued to evaluate patients with ectopic calcification due to biallelic mutations in ABCC6 causing a disease of vascular fragility (pseudoxanthoma elasticum) or ENPP1, causing fatal vascular stenosis (Generalized Calcification of Infancy). The Section remains an international referral center for individuals with ciliopathies, i.e., disorders of immotile cilia on cells; these include Joubert syndrome, Alstrom syndrome, and polycystic kidney disease. The Section has also begun studying sialic acid storage disorders. 2. The Section remains the worlds foremost center investigating clinical and basic aspects of 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 also have fatal pulmonary fibrosis. In a major collaboration with NIAAA and NCATS, Section investigators are studying the effects of a molecule that combines inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 on an HPS mouse model with pulmonary fibrosis. Section clinicians reported HPS and albinism in several Chinese children, and basic researchers characterized the effects of bleomycin on mouse models of HPS pulmonary fibrosis. Section experts continue to provide advice to physicians and patients throughout the world and contribute to HPS advocacy group conferences. 3. Section investigators remain world experts in GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Section members previously reported that the sialic acid precursor, N-acetylmannosamine (ManNAc), treats the sialic acid deficiency of a GNE mouse model. They also demonstrated safety and efficacy of ManNAc in phase I and II studies of patients with GNE myopathy. A member of the Section is now Principal Investigator of a pivotal clinical trial of ManNAc in GNE myopathy to begin October 1, 2019; that multicenter, randomized, placebo-controlled trial is funded by NIAMS as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial also has CRADA support from Leadiant Biosciences, Inc. The Section has published a statistical method of measuring disease progression in GNE myopathy and has proposed the use of ManNAc in renal glomerular disease. 4. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. This initiative, a model for Precision Medicine, provides answers to patients with mysterious conditions, and advances medical knowledge. Section members sit on the UDN Working Group, which oversees a national consortium of 12 clinical sites, a coordinating center, sequencing center, biorepository, two model organism cores, and a metabolomics core. Over the past 10 years, the NIH UDP reviewed over 4000 medical records, evaluated over 1300 patients, and diagnosing over 300 rare and novel disorders. The Section contributed to a groundbreaking New England Journal of Medicine article on the impact of a genetic diagnosis upon individuals previously undiagnosed. Section members also demonstrated the value of urinary glycome analysis in reaching a diagnosis, and developed a sophisticated pipeline of automated sequence analysis programs that illustrated the genetic burden carried by UDP probands. Finally, Section members delivered more than 15 national and international talks on the UDP in 2018, wrote a chapter on rare and undiagnosed diseases for Nelsons textbook of pediatrics, fostered expansion of the Undiagnosed Diseases Network International (UDNI) to share phenotypic and sequence data, and organized the 7th international UDNI meeting in Delhi. 5. Evaluating UDP patients has fostered new disease discovery and expansion of known genetic phenotypes. Members of the Section have spearheaded projects that revealed the genetic bases of 6 diseases; 5 investigations were published in the American Journal of Human Genetics in the past year and one in Plos Genetics. Specifically, Saul-Wilson Syndrome was shown to be caused by a monoallelic mutation in COG4, which encodes a protein in the Conserved Oligomeric Golgi complex responsible for retrograde vesicle trafficking within the Golgi. Another study described a new disorder of developmental delay, liver abnormalities, dysmorphic features, and woolly hair associated with biallelic variants in CCDC47. A third new disease, characterized by facial dysmorphisms, congenital heart defects, and neurodevelopmental abnormalities, was associated with biallelic mutations in TMEM94. A fourth disorder described by the Section was a combination of albinism, developmental delay, and organ storage caused by dysfunction of lysosomes and lysosome-related organelles. This occurred because of increased lysosomal acidity created by a gain-of-function mutation in CLCN7, encoding a chloride transporter that determines the influx of protons into lysosomes. Another case involved a boy with kinky hair reminiscent of Menkes disease, a copper deficiency disorder. The child had biallelic mutations in HEPHL1, whose function was determined by the Section to include oxidation of ferrous to ferric iron, allowing this metal to be incorporated into its apoenzymes. Finally, members of the Section described a new disorder of epilepsy, colobomas, dysmorphisms, developmental delay, and cerebellar hypoplasia due to monoallelic mutations in WDR37, which encodes a protein whose WD repeats facilitate the formation of multiprotein complexes. Section members also assisted in the description of a new disease of developmental delay, microcephaly, and brittle nails and hair due to biallelic mutations in cysteinyl tRNA synthetase. They revealed the molecular, clinical, and biochemical bases of SLC25A2 Congenital Disorder of Glycosylation, characterizing 30 previously unreported cases of this disease, and expanded the known phenotypes of COPA syndrome, a pulmonary disorder, and late infantile ceroid lipofuscinosis, a neurodevelopmental disorder due to CLN6 mutations. Section members reported a case of Early Infantile-onset Epileptic Encephalopathy 28 due to deletion of the WWOX gene related to uniparental disomy. One family had motor delays, coloboma and corneal defects associated with a novel TENM3 mutation, and another had dysarthria, ataxia, and sensory neuropathy related to COX20 variants. The Section collaborated with world experts in describing atypical autosomal dominant leukodystrophy due to an upstream deletion of lamin B1; previously reported cases were due to lamin B1 duplications.

人类生化遗传学部分的研究选择了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。该科的成员拥有几种特定疾病的专业知识。 1. 在过去的一年中，该科评估了 35 名肾病性胱氨酸病患者，在研究人员和倡导团体的国际会议上发表了讲话，回答了来自世界各地的询问，并描述了该疾病的骨骼异常。该科还照顾患有尿黑酸尿症（一种因尿黑酸积聚而导致的结缔组织疾病）和 Chediak-Higashi 病（一种巨大细胞内颗粒、致命细菌感染和淋巴细胞组织细胞增多症）的患者。国际白化病权威 OneSection 研究人员报告称，接受尼替西农（一种酪氨酸降解抑制剂）治疗的酪氨酸酶活性低的白化病个体黑色素增多。其他科室成员报告了一种罕见的组织细胞增多症（埃德海姆-切斯特病）的肺部并发症和牙齿表现。该科继续评估因 ABCC6 的双等位基因突变导致血管脆性疾病（弹性假黄瘤）或 ENPP1 导致致命性血管狭窄（婴儿全身钙化）而导致异位钙化的患者。该科仍然是纤毛病（即细胞上纤毛不动疾病）患者的国际转诊中心；这些疾病包括朱伯特综合征、阿尔斯特罗姆综合征和多囊肾病。该科还开始研究唾液酸储存障碍。 2. 该科仍然是世界上研究赫曼斯基-普德拉克综合征 (HPS) 临床和基本方面的最重要中心，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 型也有致命的肺纤维化。在与 NIAAA 和 NCATS 的一项重大合作中，该部门的研究人员正在研究一种分子对肺纤维化 HPS 小鼠模型的影响，该分子结合了诱导型一氧化氮合酶的抑制作用和内源性大麻素受体 CB1 的拮抗作用。科室临床医生报告了几名中国儿童的 HPS 和白化病，基础研究人员描述了博莱霉素对 HPS 肺纤维化小鼠模型的影响。部门专家继续为世界各地的医生和患者提供建议，并为 HPS 倡导小组会议做出贡献。 3. 部门研究人员仍然是 GNE 肌病的世界专家，GNE 肌病是一种迟发性神经肌肉疾病，由 GNE 的双等位基因突变引起，GNE 编码唾液酸生物合成中的限速酶。该部门成员之前曾报道，唾液酸前体 N-乙酰甘露糖胺 (ManNAc) 可治疗 GNE 小鼠模型的唾液酸缺乏症。他们还在 GNE 肌病患者的 I 期和 II 期研究中证明了 ManNAc 的安全性和有效性。该科的一名成员现担任 ManNAc 治疗 GNE 肌病关键临床试验的首席研究员，该试验将于 2019 年 10 月 1 日开始；这项多中心、随机、安慰剂对照试验由 NIAMS 资助，该试验是 NeuroNext（全国神经病学中心 NINDS 联盟）的一部分。该试验还得到了 Leadiant Biosciences, Inc. 的 CRADA 支持。该科已发布了一种测量 GNE 肌病疾病进展的统计方法，并提议在肾小球疾病中使用 ManNAc。 4. 该科的成员还领导 NIH 未确诊疾病计划 (UDP)，该计划是 NIH 共同基金支持的未确诊疾病网络 (UDN) 的一部分。这一举措是精准医学的典范，为患有神秘病症的患者提供了答案，并推进了医学知识。该部门成员是 UDN 工作组的成员，该工作组负责监督由 12 个临床中心、一个协调中心、测序中心、生物样本库、两个模式生物核心和一个代谢组学核心组成的国家联盟。在过去的 10 年里，NIH UDP 审查了 4000 多份医疗记录，评估了 1300 多名患者，并诊断了 300 多种罕见和新型疾病。该科为《新英格兰医学杂志》发表了一篇开创性的文章，内容涉及基因诊断对以前未诊断的个体的影响。该部门成员还证明了尿糖组分析在达成诊断方面的价值，并开发了一系列复杂的自动序列分析程序，以说明 UDP 先证者携带的遗传负担。最后，该部门成员在 2018 年就 UDP 发表了超过 15 场国内和国际演讲，为尼尔森儿科教科书撰写了有关罕见和未确诊疾病的章节，促进了国际未确诊疾病网络 (UDNI) 的扩展以共享表型和序列数据，并在德里组织了第七届国际 UDNI 会议。 5. 评估 UDP 患者促进了新疾病的发现和已知遗传表型的扩展。该部门的成员带头开展了一些项目，揭示了 6 种疾病的遗传基础；去年，《美国人类遗传学杂志》（American Journal of Human Genetics）发表了 5 项研究，《公共科学图书馆遗传学》（Plos Genetics）发表了一项研究。具体来说，Saul-Wilson 综合征是由 COG4 中的单等位基因突变引起的，COG4 编码保守寡聚高尔基复合体中的一种蛋白质，负责高尔基体内逆行囊泡运输。另一项研究描述了与 CCDC47 中双等位基因变异相关的一种新的发育迟缓、肝脏异常、畸形特征和羊毛状毛发疾病。第三种新疾病以面部畸形、先天性心脏病和神经发育异常为特征，与 TMEM94 的双等位基因突变有关。该科描述的第四种疾病是由溶酶体和溶酶体相关细胞器功能障碍引起的白化病、发育迟缓和器官储存的组合。发生这种情况的原因是 CLCN7 的功能获得性突变导致溶酶体酸度增加，CLCN7 编码一种氯离子转运蛋白，决定质子流入溶酶体。另一个病例涉及一个头发卷曲的男孩，让人想起门克斯病，一种铜缺乏症。该孩子的 HEPHL1 存在双等位基因突变，该部门确定其功能包括将亚铁氧化为三价铁，从而使这种金属能够掺入其脱辅基酶中。最后，该部门的成员描述了一种由 WDR37 的单等位基因突变引起的癫痫、缺损、畸形、发育迟缓和小脑发育不全的新疾病，WDR37 编码一种蛋白质，其 WD 重复序列促进多蛋白复合物的形成。该部门成员还协助描述了一种新疾病，即由于半胱氨酰 tRNA 合成酶的双等位基因突变而导致的发育迟缓、小头畸形以及指甲和头发脆弱。他们揭示了 SLC25A2 先天性糖基化障碍的分子、临床和生化基础，描述了 30 例以前未报告的这种疾病的病例，并扩展了 COPA 综合征（一种肺部疾病）和晚期婴儿蜡质脂褐质沉着症（一种由CLN6 突变。该组成员报告了一例由于与单亲二体性相关的 WWOX 基因缺失而导致婴儿早期发病的癫痫性脑病 28 的病例。其中一个家庭患有与新型 TENM3 突变相关的运动迟缓、缺损和角膜缺陷，另一个家庭则患有与 COX20 变异相关的构音障碍、共济失调和感觉神经病。该科与世界专家合作，描述了由于核纤层蛋白 B1 上游缺失所致的非典型常染色体显性脑白质营养不良；先前报道的病例是由于核纤层蛋白 B1 重复所致。