Peter M, Bünger K, Drop S L, Sippell W G
Department of Paediatrics, Christian-Albrechts University of Keil, Germany.
Eur J Endocrinol. 1998 Jul;139(1):96-100. doi: 10.1530/eje.0.1390096.
We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.
我们对两名先天性醛固酮减少症患者进行了分子遗传学研究。对这两名患者的最初研究于1982年发表在本杂志上。两名索引病例，一名女孩（患者1）和一名男孩（患者2），在新生儿期均出现失盐和生长发育不良。患者1的父母无亲缘关系，而患者2的父母是表亲。内分泌研究显示，患者1存在18-羟皮质酮18-氧化缺陷，患者2存在皮质酮18-羟化缺陷。两名患者的血浆醛固酮均降低，而患者1的18-羟皮质酮升高，患者2的降低。两名患者的血浆皮质酮和11-脱氧皮质酮均升高，而皮质醇及其前体在正常范围内。根据Ulick提出的命名法，这些缺陷在患者1中分别被称为皮质酮甲基氧化酶（CMO）Ⅱ型缺乏症，在患者2中为Ⅰ型缺乏症。在少数病例中已描述了编码醛固酮合酶的CYP11B2基因的遗传缺陷。在患者1中，我们仅在外显子7中鉴定出一个杂合氨基酸替代（V386A），这对酶活性没有有害影响。在患者2及其哥哥中，我们在密码子255（GAG）中鉴定出一个纯合单碱基交换（G到T），导致提前终止密码子E255X（TAG）。突变酶失去了包含血红素结合位点的五个末端外显子，因此是一种功能丧失的酶。这是第二例关于CMOⅡ型缺乏症患者在外显子和外显子-内含子边界无突变的报道，而两名CMOⅠ型缺乏症兄弟的生化表型可由患者的基因型来解释。
