The Role of a Single Formin Isoform in the Limb and Renal Phenotypes of Limb Deformity
The Role of a Single Formin Isoform in the Limb and Renal Phenotypes of Limb Deformity
复制标题
单一福明亚型在肢体畸形的肢体和肾脏表型中的作用
作者：
A. Wynshaw;Gabriella Ryan;C. Deng;D. Chan;L. Jackson‐Grusby;D. Larson;J. Dunmore;P. Leder
小鼠肢体畸形（ld）位点的突变是导致完全渗透性肢体畸形和不完全渗透性肾脏发育和/或发育不良的多效表型的原因。ld位点编码一个复杂的mRNA和蛋白质同工异构体家族。材料和方法为了研究其中一个更突出的异构体，异构体IV的作用，我们通过基因靶向特异性地消除了它。结果与其他突变型ld小鼠一样，携带这种亚型IV破坏的纯合子小鼠表现出不完全渗透性肾发育，但四肢完全正常。全载原位杂交表明，这种靶向破坏是特异性的亚型IV，不干扰其他旧亚型的表达。ld的同工型iv被破坏的等位基因不以与其外显率一致的方式补充其他ld等位基因的肾发育表型，并且像同工型iv缺陷的小鼠一样，这些复合杂合子具有正常的肢体。对其他老突变等位基因的双胍异构体IV的序列分析未发现突变等位基因起源菌株的氨基酸变化。结论IV型异构体的破坏足以引起老年突变小鼠的肾发育不全表型，但不足以引起老年突变小鼠的肢体表型。该异构体的结构突变只是导致肾脏表型的几种遗传机制之一，因为该异构体的氨基酸变化未被检测到。这些结果表明，该基因是肢体畸形的基因，并且可变的异构体表达可能在产生多效性表型中起作用。
BackgroundMutations of the murine limb deformity (ld) locus are responsible for a pleiotropic phenotype of completely penetrant limb malformations and incompletely penetrant renal agenesis and/or dysgenesis. The ld locus encodes a complex family of mRNA and protein isoforms.Materials and MethodsTo examine the role of one of the more prominent of these isoforms, isoform IV, we specifically eliminated it by gene targeting.ResultsUnlike other mutant ld mice, homozygous mice bearing this isoform IV disruption display incompletely penetrant renal agenesis, but have perfectly normal limbs. Whole mount in situ hybridization demonstrated that this targeted disruption was specific for isoform IV and did not interfere with the expression of other ld isoforms. The isoform IV-disrupted allele of ld does not complement the renal agenesis phenotype of other ld alleles, in a manner consistent with its penetrance, and like the isoform IV-deficient mice, these compound heterozygotes have normal limbs. Sequence analysis of formin isoform IV in other ld mutant alleles did not detect any amino acid changes relative to the strain of origin of the mutant allele.ConclusionsThus, the disruption of isoform IV is sufficient for the renal agenesis phenotype, but not the limb phenotype of ld mutant mice. Structural mutations in this isoform are only one of several genetic mechanisms leading to the renal phenotype, since amino acid changes in this isoform were not detected. These results demonstrate that this gene is limb deformity, and that variable isoform expression may play a role in generating the pleiotropic ld phenotype.
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辐射诱导的小鼠 2 号染色体结构重排导致肢体畸形和刺鼠基因座突变的分子和遗传特征。
DOI：
10.1073/pnas.87.7.2588
发表时间：
1990
影响因子：
11.1
作者：
Woychik,RP;Generoso,WM;Russell,LB;Cain,KT;Cacheiro,NL;Bultman,SJ;Selby,PB;Dickinson,ME;Hogan,BL;Rutledge,JC
通讯作者：
Rutledge,JC
影响因子：
10.5
作者：
PELLETIER, J;SCHALLING, M;HOUSMAN, D
通讯作者：
HOUSMAN, D
影响因子：
4.6
作者：
V. Pachnis;B. Mankoo;F. Costantini
通讯作者：
V. Pachnis;B. Mankoo;F. Costantini
转基因小鼠品系中 ld 基因座的插入突变（再次！）。
DOI：
--
发表时间：
1990
期刊：
Mouse genome
影响因子：
--
作者：
Messing,A;Behringer,RR;Slapak,JR;Lemke,G;Palmiter,RD;Brinster,RL
通讯作者：
Brinster,RL