据一项发表于10月15日American Journal of Human Genetics的研究报告,华盛顿大学医学院的研究人员在四个新生儿基因组中新发现一个共同的突变基因,这四个新生儿的肺部,消化道,泌尿系统,皮肤,骨骼和肌肉发育异常,并且都出现皮肤疏松(cutis laxa)。其中三名患者在在2岁之前死于呼吸衰竭。
该基因或许对开发治疗慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)有潜在影响。
研究人员对缺失LTBP4基因的基因工程鼠进行研究,该缺陷型小鼠的皮肤组织电镜下也出现结缔组织紊乱,与上述的其中一名新生儿症状相似,并且这名新生儿同时还出现致命性肺部并发症以及消化道和泌尿疾病。
基于上述观察,研究人员对LTBP4基因进行测序,证实该基因发生了突变。
研究人员确定,该研究是首次对这种症状进行报道,因此,课题组将这种症状命名为Urban-Rifkin-Davis综合症(Urban-Rifkin-Davis Syndrome)。(生物谷Bioon.com)
生物谷推荐原始出处:
The American Journal of Human Genetics, 15 October 2009 doi:10.1016/j.ajhg.2009.09.013
Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development
Zsolt Urban1, 2, 3, , , Vishwanathan Hucthagowder1, Nura Schürmann1, Vesna Todorovic4, Lior Zilberberg4, Jiwon Choi6, Carla Sens1, Chester W. Brown7, 8, Robin D. Clark9, Kristen E. Holland10, Michael Marble11, 12, Lynn Y. Sakai13, Branka Dabovic4, Daniel B. Rifkin4, 5 and Elaine C. Davis6
1 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
3 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
4 Department of Cell Biology, New York University Langone School of Medicine, New York, NY 10016, USA
5 Department of Medicine, New York University Langone School of Medicine, New York, NY 10016, USA
6 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
8 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
9 Department of Pediatrics, Loma Linda School of Medicine, Loma Linda, CA 92354, USA
10 Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
11 Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA
12 Children's Hospital of New Orleans, New Orleans, LA 70118, USA
13 Department of Biochemistry and Molecular Biology, Shriners Hospital for Children, Oregon Health & Science University, Portland, OR 97239, USA
We report recessive mutations in the gene for the latent transforming growth factor-β binding protein 4 (LTBP4) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis, enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Four of the five identified LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 mRNA. Impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased transforming growth factor-β (TGF-β) activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by the disease. These molecular defects were associated with blocked alveolarization and airway collapse in the lung. Our results show that coupling of TGF-β signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4.