Huq A H, Lovell R S, Ou C N, Beaudet A L, Craigen W J
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Hum Mol Genet. 1997 Oct;6(11):1803-9. doi: 10.1093/hmg/6.11.1803.
Glycerol kinase is an X chromosome-encoded enzyme involved in the metabolism of endogenous and dietary glycerolipids. The physiological significance of its activity in mammals is not well understood. Glycerol kinase deficiency in humans occurs as an isolated enzyme deficiency or as part of a contiguous gene deletion syndrome in variable association with Duchenne muscular dystrophy and adrenal hypoplasia congenita. Isolated glycerol kinase deficiency has an inconstant phenotype, ranging from asymptomatic hyperglycerolemia to a severe metabolic disorder with growth and psychomotor retardation. Although intragenic mutations were reported recently, the pathophysiological basis for the phenotypic variability remains unknown. To understand better the physiological significance of glycerol kinase and the pathophysiology of its deficiency, we generated glycerol kinase-deficient mice by gene targeting. Mutant male mice appear normal at birth, but exhibit postnatal growth retardation, altered fat metabolism with profound hyperglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis and death by 3-4 days of age. Heterozygous females are healthy and biochemically normal. The biochemical features observed in glycerol kinase-deficient mice provide the basis for further investigations into the pathogenesis of the human disorder.
甘油激酶是一种由X染色体编码的酶，参与内源性和膳食甘油脂质的代谢。其在哺乳动物体内活性的生理意义尚未完全明确。人类甘油激酶缺乏症表现为孤立的酶缺乏，或作为一种连续性基因缺失综合征的一部分，与杜氏肌营养不良症和先天性肾上腺发育不全存在不同程度的关联。孤立性甘油激酶缺乏症具有不恒定的表型，从无症状的高甘油血症到伴有生长发育和精神运动发育迟缓的严重代谢紊乱。尽管最近报道了基因内突变，但表型变异性的病理生理基础仍然未知。为了更好地理解甘油激酶的生理意义及其缺乏症的病理生理学，我们通过基因靶向技术培育出了甘油激酶缺陷型小鼠。突变雄性小鼠出生时外观正常，但出生后生长发育迟缓，脂肪代谢改变，伴有严重的高甘油血症和游离脂肪酸升高，自主合成糖皮质激素，并在3 - 4日龄时死亡。杂合子雌性小鼠健康且生化指标正常。在甘油激酶缺陷型小鼠中观察到的生化特征为进一步研究人类疾病的发病机制提供了基础。
