Genetic Control of Phospholipid Biosynthesis and Muscular Dystrophy

磷脂生物合成和肌营养不良症的遗传控制

基本信息

批准号：
8130650
负责人：
GREGORY A. COX
金额：
$ 33.26万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-14 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8130650
关键词：
22q13.3 Adult Affect Alleles Anabolism Birth Brazil Candidate Disease Gene Cells Cessation of life Choline Choline Kinase Choline-Phosphate Cytidylyltransferase Clinical Collaborations DNA Defect Disease Disease Progression Electron Transport Enzymes Eukaryotic Cell Family Forelimb Foundations Genes Genetic Goals Hindlimb Histopathology Human Japan Lead Lecithin Limb-Girdle Muscular Dystrophies Link Lipids Maintenance Membrane Membrane Potentials Membrane Proteins Merosin Mitochondria Molecular Molecular Genetics Mus Muscle Muscle Weakness Muscular Dystrophies Mutant Strains Mice Mutation Myoblasts Nature Nuclear Envelope Pathway interactions Patients Phenotype Phospholipids Phosphorylation Phosphorylcholine Physiology Population Process Proteins Sampling Sarcolemma Severities Skeletal Muscle Testing Tissues Transgenic Mice Universities cohort congenital muscular dystrophy disability disease phenotype gait examination genetic linkage human disease in vivo mitochondrial dysfunction mitochondrial membrane muscle degeneration muscle transplantation mutant novel null mutation premature protein function wasting

项目摘要

DESCRIPTION (provided by applicant): Muscular dystrophies include a diverse group of genetically heterogeneous disorders that affect 1:2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation causing a progressive muscular dystrophy with a rostral-to-caudal gradient of severity. We have identified the rmd mutation as a 1.6 kb deletion within the choline kinase beta (Chkb) gene, resulting in loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes catalyzing the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine (PC). PC is the most abundant phospholipid in eukaryotic cells and it serves not only as a structural foundation for membrane bilayers, but also as a precursor for several lipid messengers. While mutant rmd mice show dramatically decreased CHK activity in all tissues examined, the disease is only evident in skeletal muscle tissues which display a 30% reduction in total PC content. Several muscular dystrophy mutations have been identified in membrane-associated proteins that function at the sarcolemma or nuclear envelope. However, the rmd mutant mouse is the first to demonstrate that alterations in membrane phospholipid composition can result in a progressive muscular dystrophy phenotype. The aims of our proposal are: 1) To test the hypothesis that rmd muscular dystrophy is due to a cell autonomous loss of CHKB in skeletal muscles. 2) To test the hypothesis that mitochondrial dysfunction underlies the progressive skeletal muscle degeneration in primary mouse myoblast cultures and adult skeletal muscles. 3) To screen a large Brazilian population of congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) patients for mutations in the orthologous human CHKB gene. In collaboration with Dr. Mayana Zatz, we will test for human CHKB mutations in DNA samples from patients that have previously been screened and eliminated for known molecular causes of muscular dystrophy. The primary goals of this proposal are to use the novel mouse rmd mutation to explore the cell-autonomous nature of this defect in skeletal muscles, to dissect the molecular and genetic mechanisms of muscular degeneration and to determine the range of defects in CHKB that underlie previously unidentified human muscular dystrophies. The rmd mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy and may reveal unique entry points in which to intervene in the disease process.

描述（由申请人提供）：肌营养不良症包括一组不同的遗传异质性疾病，影响全球 1:2000 的出生率。这些疾病的特点是进行性肌肉无力和消耗，导致严重残疾并常常过早死亡。喙尾肌营养不良症（rmd）是一种新的隐性小鼠突变，导致进行性肌营养不良，其严重程度从头尾到尾部呈梯度变化。我们已将 rmd 突变鉴定为胆碱激酶β (Chkb) 基因内的 1.6 kb 缺失，导致 CHKB 蛋白和酶活性丧失。 CHKB 是两种哺乳动物胆碱激酶 (CHK) 酶之一，在主要膜磷脂磷脂酰胆碱 (PC) 的生物合成中催化胆碱磷酸化为磷酸胆碱。 PC 是真核细胞中最丰富的磷脂，它不仅作为膜双层的结构基础，而且还是多种脂质信使的前体。虽然突变 rmd 小鼠在所有检查的组织中都显示出 CHK 活性显着降低，但这种疾病仅在骨骼肌组织中明显，其总 PC 含量减少了 30%。在肌膜或核膜发挥作用的膜相关蛋白中已鉴定出几种肌营养不良症突变。然而，rmd 突变小鼠首次证明膜磷脂成分的改变可导致进行性肌营养不良症表型。我们提案的目的是： 1) 检验 rmd 肌营养不良症是由于骨骼肌中 CHKB 细胞自主丢失所致的假设。 2) 检验原代小鼠成肌细胞培养物和成年骨骼肌中线粒体功能障碍是进行性骨骼肌变性的假设。 3) 对巴西大量先天性肌营养不良症（CMD）和肢带型肌营养不良症（LGMD）患者进行直系同源人类 CHKB 基因突变筛查。我们将与 Mayana Zatz 博士合作，测试患者 DNA 样本中的人类 CHKB 突变，这些患者之前已针对已知的肌营养不良分子原因进行了筛查和消除。该提案的主要目标是利用新型小鼠 rmd 突变来探索骨骼肌中这种缺陷的细胞自主性质，剖析肌肉变性的分子和遗传机制，并确定先前存在的 CHKB 缺陷范围不明的人类肌营养不良症。 rmd 小鼠首次证明了导致肌营养不良的磷脂生物合成酶的缺陷，并可能揭示干预疾病过程的独特切入点。