Human Biochemical Genetics

人类生化遗传学

基本信息

批准号：
6671802
负责人：
William Allen Gahl
金额：
--
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
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

项目摘要

The Section on Human Biochemical Genetics investigates rare and informative inborn errors of metabolism, including Hermansky?Pudlak syndrome, cystinosis, and alkaptonuria. 1. Members of the Section continue to discover mutations in the four known genes causing HPS, and to search for new genes responsible for the disease. In collaboration with other scientists, they have helped develop an assay for detecting serotonin in platelets, evaluated a clotting analyzer for humans with platelet defects, and delineated the radiographic features of HPS patients with pulmonary fibrosis. The Section has examined, cared for,and investigated 120 HPS patients to date. 2. Members of the Section follow approximately 60 patients with cystinosis, some before and some after renal transplantation. They perform mutation analysis on patients new to the protocol, accumulate longitudinal data on treatment regimens, and detect early and late complications of cystinosis. In collaboration with physicians in the National Eye Institute, the Section has helped to describe anterior segment complications of cystinosis and retinal visualization in cystinosis using indocyanine green videoangiography. A study of a new formulation of cysteamine eyedrops was also promulgated by the Section. 3. Alkaptonuria results from accumulation of homogentisic acid, an intermediate in tyrosine degradation, due to deficiency of homogentisate 1,2-dioxygenase. The symptoms include joint and cardiac valve deterioration beginning in mid-life. We have now examined and investigated more than 60 alkaptonuria patients on clinical, biochemical, and molecular grounds. We have identified 90% of the genetic mutations causing alkaptonuria in our patients, and have described a man with alkaptonuria and diabetic nephropathy whose renal disease exacerbated his ochronosis. Two women with alkaptonuria were given low doses of nitisinone, a drug which inhibits the enzyme producing homogentisic acid. Although plasma tyrosine levels rose dramatically, the lowering of homogentisic acid production provides proof of principle for the use of nitisinone in alkaptonuria. 4. The Section also pursues a variety of other rare disorders of human metabolism. Members of the Section have identified the gene and the mutations responsible for type III 3-methylglutaconic aciduria in Iraqi-Jewish and non-Iraqi-Jewish patients. They have described a patient with Griscelli syndrome and neurological involvement caused by mutations in rab27a rather than the expected gene, myosin 5A. In collaboration with other investigators, they have reported patients with lysosomal free sialic acid storage due to mutations in the gene encoding the lysosomal sialic acid transporter. The Section remains the world?s referral laboratory for diagnosing sialuria and other disorders of free sialic acid metabolism.

人类生物化学遗传学部分研究了罕见且信息丰富的新陈代谢错误，包括Hermansky？Pudlak综合征，囊肿性和藻核综合症。 1。本节的成员继续发现引起HP的四个已知基因突变，并寻找负责该疾病的新基因。他们与其他科学家合作，帮助开发了一种用于检测血小板中5-羟色胺的测定法，评估了患有血小板缺陷的人类的凝血分析仪，并描述了肺纤维化的HPS患者的放射线学特征。迄今为止，该部分已经检查，照顾和研究了120名HPS患者。 2。本节的成员遵循大约60例囊肿性患者，其中一些肾脏移植后和一些患者。他们对方案新的患者进行突变分析，积累治疗方案的纵向数据，并检测到膀胱变性的早期和晚期并发症。该部分与国家眼科研究所的医生合作，有助于描述使用吲哚美氨酸绿色视频摄影术在伴随着囊肿性的囊肿和视网膜可视化的前部并发症。该部分还颁布了对cysteamine eiedrops的新配方的研究。 3。烷酸核酸脂蛋白尿素是由于均匀剂量的1,2-二加氧酶的缺乏而导致的均酸（酪氨酸降解中间体）的积累。症状包括从中期开始的关节和心脏瓣膜恶化。现在，我们已经检查并研究了60多名烷基核酸菌患者在临床，生化和分子基础上。我们已经确定了90％的遗传突变，导致患者的藻尿症，并描述了一个患有烷酸核酸藻尿和糖尿病性肾病的人，其肾脏疾病加剧了他的效率。给出了两名患有烷基核酸藻尿的妇女，低剂量的硝酸盐，一种抑制产生均匀酸的酶的药物。尽管血浆酪氨酸水平急剧上升，但同叶酸产生的降低提供了用于在碱中使用硝酸盐的原理证明。 4。本节还追求了人类代谢的其他各种罕见疾病。本节的成员已经确定了伊拉克犹太人和非伊拉克犹太人患者的III型3-甲基谷霉素酸尿的基因和突变。他们描述了由Rab27a突变而不是预期的基因肌球蛋白5a引起的Griscelli综合征和神经学参与的患者。他们与其他研究者合作，报告了由于编码溶酶体唾液酸转运蛋白的基因突变而导致的溶酶体游离唾液酸储存的患者。该节仍然是诊断唾液酸和其他唾液酸代谢的其他疾病的世界推荐实验室。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sialic acid storage disease of the Salla phenotype in American monozygous twin female sibs.

美国单卵双胞胎女性同胞中 Salla 表型的唾液酸贮积病。

DOI：
10.1002/ajmg.a.10246
发表时间：
2003
期刊：
American journal of medical genetics. Part A
影响因子：
0
作者：
Martin,RickA;Slaugh,Rachel;Natowicz,Marvin;Pearlman,Kayla;Orvisky,Eduard;Krasnewich,Donna;Kleta,Robert;Huizing,Marjan;Gahl,WilliamA
通讯作者：
Gahl,WilliamA

Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes.

DOI：
10.2174/1566524023362357
发表时间：
2002-08-01
期刊：
Current molecular medicine
影响因子：
2.5
作者：
Huizing, M;Gahl, W A
通讯作者：
Gahl, W A

Characterization of a partial pseudogene homologous to the Hermansky-Pudlak syndrome gene HPS-1; relevance for mutation detection.

与 Hermansky-Pudlak 综合征基因 HPS-1 同源的部分假基因的表征；

DOI：
10.1007/s004390051053
发表时间：
2000
期刊：
Human genetics
影响因子：
5.3
作者：
Huizing,M;Anikster,Y;Gahl,WA
通讯作者：
Gahl,WA

A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.

灰血小板综合征 (GPS) 的新遗传分离株：临床、细胞和血液学特征。

DOI：
10.1006/mgme.2001.3247
发表时间：
2001
期刊：
Molecular genetics and metabolism
影响因子：
3.8
作者：
Falik-Zaccai,TC;Anikster,Y;Rivera,CE;Horne3rd,MK;Schliamser,L;Phornphutkul,C;Attias,D;Hyman,T;White,JG;Gahl,WA
通讯作者：
Gahl,WA

Genotypes and phenotypes.

基因型和表型。

DOI：
10.1097/00125817-200111000-00001
发表时间：
2001
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
0
作者：
Gahl,WA
通讯作者：
Gahl,WA