Genetic analysis of Pycr1 and Pycr2 in mice.
Genetic analysis of Pycr1 and Pycr2 in mice.
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小鼠 Pycr1 和 Pycr2 的遗传分析。
DOI：
10.1093/genetics/iyab048
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发表时间：
2021
期刊：
影响因子：
3.3
通讯作者：
Burgess,RobertW
中科院分区：
文献类型：
--
作者：
Stum,MorganeG;Tadenev,AbigailLD;Seburn,KevinL;Miers,KathyE;Poon,PakP;McMaster,ChristopherR;Robinson,Carolyn;Kane,Coleen;Silva,KathleenA;Cliften,PaulF;Sundberg,JohnP;Reinholdt,LauraG;John,SimonWM;Burgess,RobertW
脯氨酸生物合成的最后一步由三种吡咯啉-5-羧酸还原酶PYCR 1、PYCR 2和PYCR 3催化，其将吡咯啉-5-羧酸（P5 C）转化为脯氨酸。人类PYCR 1和ALDH 18 A1（P5 C合成酶）的突变导致皮肤拉克萨（CL），而PYCR 2的突变导致低髓鞘化脑白质营养不良10（HLD 10）。在此，我们研究了小鼠Pycr 1和Pycr 2的遗传学。一个无效等位基因的Pycr 1没有表现出珠被或CL相关的表型。我们还研究了一种新的化学诱导突变inPycr 2。Pycr 2基因隐性功能缺失突变的小鼠表现出与神经和神经肌肉疾病一致的表型，包括体重减轻、脊柱后凸和后肢紧握。周围神经系统基本上未受影响，周围神经中仅有轻度轴突萎缩。Pycr 2突变小鼠皮下脂肪的严重损失使人联想到CL样表型，但没有观察到弹性蛋白异常等主要特征。pydPycr 2突变小鼠的白色血细胞计数减少，脂质代谢改变，提示全身性代谢紊乱。PYCR 1和PYCR-2具有相似的酶活性和细胞活性，并且与先前的研究一致，两者都定位于成纤维细胞的线粒体中。PYCR-1和-2都能够补充Pro3的损失，Pro3是将P5 C转化为脯氨酸的酵母酶，证实了它们作为P5 C还原酶的活性。在小鼠中，Pycr 1; Pycr 2双突变体与任一单突变体相比是亚存活的和不健康的，表明基因在很大程度上是功能冗余的。在Pycr 2突变小鼠的血清或皮肤成纤维细胞培养物的裂解物中，脯氨酸水平没有降低，前体也没有增加，但将Pycr 2突变小鼠置于无脯氨酸饮食中使表型恶化。因此，Pycr 1和-2在脯氨酸生物合成中具有冗余功能，它们的缺失使脯氨酸成为半必需氨基酸。这些发现对于理解CL和HLD 10的遗传学以及在小鼠中建模这些疾病具有意义。
The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to proline. Mutations in humanPYCR1andALDH18A1(P5C Synthetase) cause Cutis Laxa (CL), whereas mutations inPYCR2cause hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics ofPycr1 and Pycr2in mice. A null allele ofPycr1did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation inPycr2. Mice with recessive loss-of-function mutations inPycr2showed phenotypes consistent with neurological and neuromuscular disorders, including weight loss, kyphosis, and hind-limb clasping. The peripheral nervous system was largely unaffected, with only mild axonal atrophy in peripheral nerves. A severe loss of subcutaneous fat inPycr2 mutant mice is reminiscent of a CL-like phenotype, but primary features such as elastin abnormalities were not observed. AgedPycr2mutant mice had reduced white blood cell counts and altered lipid metabolism, suggesting a generalized metabolic disorder. PYCR1 and -2 have similar enzymatic and cellular activities, and consistent with previous studies, both were localized in the mitochondria in fibroblasts. BothPYCR1and-2were able to complement the loss of Pro3, the yeast enzyme that converts P5C to proline, confirming their activity as P5C reductases. In mice,Pycr1; Pycr2double mutants were sub-viable and unhealthy compared to either single mutant, indicating the genes are largely functionally redundant. Proline levels were not reduced, and precursors were not increased in serum fromPycr2mutant mice or in lysates from skin fibroblast cultures, but placingPycr2mutant mice on a proline-free diet worsened the phenotype. Thus,Pycr1and-2have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid. These findings have implications for understanding the genetics of CL and HLD10, and for modeling these disorders in mice.
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影响因子：
2
作者：
Dasouki, Majed;Markova, Dessislava;Chu, Mon-Li
通讯作者：
Chu, Mon-Li
PYCR2突变会导致小头畸形的致命综合征和未能繁殖。
影响因子：
11.2
作者：
Zaki MS;Bhat G;Sultan T;Issa M;Jung HJ;Dikoglu E;Selim L;G Mahmoud I;Abdel-Hamid MS;Abdel-Salam G;Marin-Valencia I;Gleeson JG
通讯作者：
Gleeson JG
灵长类动物进化过程中原弹性蛋白基因两个相邻外显子的连续丢失
影响因子：
3.9
作者：
Z. Szabó;S. Levi;A. Christiano;Carole Struminger;M. Stoneking;M. Batzer;C. Boyd
通讯作者：
C. Boyd
影响因子：
3.4
作者：
Wooley, CM;Sher, RB;Seburn, KL
通讯作者：
Seburn, KL
影响因子：
2.9
作者：
Tanner JJ;Fendt SM;Becker DF
通讯作者：
Becker DF