Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders
Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders
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DOI：
10.1086/302103
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发表时间：
1998-11-01
影响因子：
9.8
通讯作者：
Gould, SJ
中科院分区：
文献类型：
--
作者：
Chang, CC;Gould, SJ
过氧化物酶体生物发生障碍（PBDs）是一组以智力低下和过氧化物酶体基质蛋白输入缺陷为特征的常见致死性遗传性疾病。已知PEX 12中的突变是来自PBD的互补组3的两名患者的疾病的基础。在这里，我们表明，所有患者从这个组携带突变的两个等位基因的PEX 12。PEX 12基因型与相应PBD患者的临床和细胞表型之间的比较表明，在该组PBD中基因型与表型之间存在相对直接的关系，使得PEX 12功能的丧失导致更严重的细胞和临床表型。一个患者线表现出相对轻微的临床和细胞表型，是每个PEX 12等位基因上两个看似严重突变的复合杂合子，PEX 12，存在于患者细胞中的mRNA仅来源于一个等位基因，该等位基因在PEX 12编码区的早期携带2-bp缺失，c.26，27 Δ。该mRNA的推导蛋白产物将仅包含蛋白质的前8个氨基酸，然而该突变体PEX 12 cDNA在功能互补测定中显示出显著的PEX 12活性。令人惊讶的是，PEX 12/c.26，27 Delta cDNA在体外指导29-kD PEX 12蛋白的合成，这一结果与下游AUG密码子处的翻译起始一致。转染研究证实了来自PEX 12/c.26，27 Delta等位基因的类似大小的PEX 12蛋白的表达。似乎内部AUG密码子的翻译起始可以调节疾病表型，并且当编码区早期的严重突变导致意外的温和表型时，应该考虑在内。
The peroxisome-biogenesis disorders (PBDs) are a set of often lethal genetic diseases characterized by mental retardation and defective peroxisomal matrix protein import. Mutations in PEX12 are known to underlie the disease in two patients from complementation group 3 of the PBDs. Here we show that all patients from this group carry mutations on both alleles of PEX12. A comparison between PEX12 genotypes and the clinical and cellular phenotypes of rite corresponding PBD patients suggests a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of PEX12 function Leads to more-severe cellular and clinical phenotypes, However, one patient wire presented relatively mild clinical and cellular phenotypes was a compound heterozygote for two seemingly severe mutations on each PEX12 allele, PEX12, mRNA present in the patient's cells was derived from only one allele, the one that carried a 2-bp deletion early in the PEX12 coding region, c.26,27 Delta. The deduced protein product of this mRNA would contain only the first eight amino acids of the protein, and yet this mutant PEX12 cDNA displayed significant PEX12 activity in a functional complementation assay. Surprisingly, the PEX12/c.26,27 Delta cDNA directed the synthesis of a 29-kD PEX12 protein in vitro, a result that is consistent with translation initiation at a downstream AUG codon, Transfection studies confirmed the expression of similarly sized PEX12 proteins from the PEX12/c.26,27 Delta allele, Thus, it appears that translation initiation at internal AUG codons may modulate disease phenotypes and should be considered whenever unexpectedly mild phenotypes result from severe mutations early in the coding region.