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，以深入了解细胞机制并照顾被忽视的罕见疾病患者。该科成员在若干具体疾病方面具有专门知识。1. 在过去的一年中，该部门评估了35名肾病胱氨酸病患者，在国际调查人员和倡导团体会议上发言，回应了来自世界各地的询问，并描述了该疾病的骨骼异常。该科还照顾患有尿尿症（由于均质酸积累引起的结缔组织疾病）和Chediak-Higashi病（细胞内巨大颗粒、致命细菌感染和淋巴细胞组织细胞增多症的疾病）的患者。一位国际白化病研究权威Section研究者报道，在酪氨酸酶活性较低的白化病患者中，使用nitisinone（酪氨酸降解抑制剂）治疗后，黑色素增加。其他科成员报告了一种罕见的组织细胞增多症，厄德海姆-切斯特病的肺部并发症和牙齿表现。该小组继续评估由于ABCC6双等位基因突变导致血管易碎性疾病（弹性假黄瘤）或ENPP1导致致命血管狭窄（婴儿期全身性钙化）的异位钙化患者。该科仍然是患有纤毛病（即细胞上不动纤毛紊乱）的个人的国际转诊中心；这些疾病包括Joubert综合征、Alstrom综合征和多囊肾病。该科还开始研究唾液酸储存障碍。2. 该科仍然是世界上最重要的研究Hermansky-Pudlak综合征（HPS）临床和基础方面的中心，HPS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型、2型和4型也有致命性肺纤维化。在与NIAAA和NCATS的主要合作中，Section研究人员正在研究一种结合抑制诱导性一氧化氮合酶和内源性大麻素受体CB1拮抗剂的分子对肺纤维化HPS小鼠模型的影响。部分临床医生报道了几个中国儿童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。科专家继续向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. 部分研究人员仍然是GNE肌病的世界专家，这是一种由GNE双等位基因突变引起的迟发性神经肌肉疾病，编码唾液酸生物合成中的限速酶。章节成员先前报道了唾液酸前体n -乙酰甘露糖胺（ManNAc）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。该部门的一名成员现在是ManNAc在GNE肌病中的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、安慰剂对照的试验是由NIAMS资助的，作为全国神经病学中心联盟neuroonext的一部分。该试验还得到了leadant Biosciences， Inc.的CRADA支持。该科发表了一种测量GNE肌病疾病进展的统计方法，并建议在肾小球疾病中使用甘乃克。4. 该科成员还领导NIH未确诊疾病计划（UDP），该计划是由NIH共同基金支持的未确诊疾病网络（UDN）的一部分。这一举措是精准医疗的典范，为患有神秘疾病的患者提供了答案，并推动了医学知识的发展。该组成员是UDN工作组的成员，该工作组负责监督一个由12个临床站点、一个协调中心、测序中心、生物储存库、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，诊断了300多种罕见和新型疾病。该科贡献了一篇开创性的新英格兰医学杂志文章，关于基因诊断对以前未诊断的个体的影响。小组成员还展示了尿糖分析在诊断中的价值，并开发了一个复杂的自动化序列分析程序管道，说明了UDP先证所携带的遗传负担。最后，科成员在2018年举办了超过15次关于UDP的国内和国际会议，为尼尔森儿科教科书撰写了罕见和未诊断疾病章节，促进了未诊断疾病国际网络（UDNI）的扩展，以共享表型和序列数据，并组织了第七届国际UDNI会议。评估UDP患者促进了新疾病的发现和已知遗传表型的扩展。该科成员率先开展了揭示6种疾病遗传基础的项目；去年有5项研究发表在《美国人类遗传学杂志》上，1项发表在《公共科学图书馆遗传学》上。具体来说，索尔-威尔逊综合征被证明是由COG4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CCDC47中与双等位基因变异相关的发育迟缓、肝脏异常、畸形特征和羊毛状头发的新疾病。第三种以面部畸形、先天性心脏缺陷和神经发育异常为特征的新疾病与TMEM94的双等位基因突变有关。本节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。这是因为CLCN7的功能获得突变导致溶酶体酸度增加，编码一种氯转运体，决定质子流入溶酶体。另一个病例涉及一个男孩，他的头发卷曲，让人想起门克斯病，一种缺铜症。该患儿在HEPHL1中有双等位基因突变，其功能被切片确定为包括亚铁氧化为铁，使这种金属被纳入其载脂蛋白酶。最后，该组成员描述了由WDR37单等位基因突变引起的癫痫、结肠瘤、畸形、发育迟缓和小脑发育不全等新疾病，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。该科成员还协助描述了一种由半胱氨酸tRNA合成酶双等位基因突变引起的发育迟缓、小头畸形、指甲和头发脆性的新疾病。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例以前未报道过的这种疾病的特征，并扩大了COPA综合征（一种肺部疾病）和晚期婴儿蜡样脂褐质病（一种由CLN6突变引起的神经发育障碍）的已知表型。该科成员报告了一例由WWOX基因缺失引起的早期婴儿癫痫性脑病28。一个家庭有与新的TENM3突变相关的运动迟缓、缺损和角膜缺陷，另一个家庭有与COX20变异相关的构音障碍、共济失调和感觉神经病变。该科与世界专家合作，描述了由于上游层粘连蛋白B1缺失引起的非典型常染色体显性白质营养不良；以前报告的病例是由于层粘连蛋白B1重复。

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.