Mutations in PTF1A cause pancreatic and cerebellar agenesis
Mutations in PTF1A cause pancreatic and cerebellar agenesis
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DOI：
10.1038/ng1475
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发表时间：
2004-12-01
期刊：
影响因子：
30.8
通讯作者：
Houlston, RS
中科院分区：
文献类型：
--
作者：
Sellick, GS;Barker, KT;Houlston, RS
患有永久性新生儿糖尿病的个体通常在生命的前三个月内出现，需要胰岛素治疗（1，2）。我们最近在一个巴基斯坦近亲家庭的全基因组连锁搜索中发现了染色体10 p13-p12.1上的一个位点，该位点与胰腺和小脑发育不全相关的永久性新生儿糖尿病有关（3）。在这里，我们报告了进一步的连锁分析，这个家庭和第二个家庭的北方欧洲血统分离一个相同的表型。定位克隆鉴定了编码胰腺转录因子1 α的基因PTF 1A中的突变705 insG和C886 T，作为致病序列变化。这两种突变都导致表达的PTF 1A蛋白C-末端截短到基本螺旋环螺旋结构域。使用最小PTF 1A缺失突变体的报告基因研究表明，缺失区域定义了一个新的结构域，这对该蛋白质的功能至关重要。已知PTF 1A在哺乳动物胰腺发育中起作用（4，5），受影响个体的临床表型表明该蛋白质是小脑神经发生的关键调节因子。PTF 1A在正常小脑发育中的重要作用通过Ptf 1a（-/-）小鼠的详细神经病理学分析得到证实。
Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment(1,2). We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family(3). Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development(4,5), and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice.