Leary Scot C, Mattman Andre, Wai Timothy, Koehn David C, Clarke Lorne A, Chan Suzanne, Lomax Brenda, Eydoux Patrice, Vallance Hilary D, Shoubridge Eric A
Department of Pathology and Laboratory Medicine, Children's & Women's Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada V6H 3V4.
Mol Genet Metab. 2006 Sep-Oct;89(1-2):129-33. doi: 10.1016/j.ymgme.2006.04.016. Epub 2006 Jun 9.
Mutations in SCO2, a metallochaperone involved in mitochondrial copper delivery, are associated with early onset, fatal hypertrophic cardiomyopathy. All reported patients carry at least one copy of the common 1541G>A (E140K) mutation. Whereas patients with one copy of the E140K allele, in combination with a more deleterious mutation, follow a severe clinical course, patients homozygous for the E140K mutation have a delayed onset of disease and a more prolonged survival. Here, we have investigated a patient who appeared homozygous for the common 1541G>A mutation based on DNA sequencing and restriction enzyme analysis of a PCR product, yet presented with early onset, severe cardiomyopathy. Restriction enzyme analysis of parental DNA revealed that the mother was heterozygous for 1541G>A, while the father was homozygous wild-type. The patient showed biparental inheritance for microsatellite markers spanning the length of chromosome 22, making isodisomy unlikely. Sequencing of several single nucleotide polymorphisms within the 5'-UTR, intron and single exon of the SCO2 gene was uninformative; however, a 16 bp deletion within the intron was present in the patient and the mother, but not the father. Restriction enzyme analysis confirmed that the mother was heterozygous and that the patient was hemizygous for the deletion. Southern blot, Northern blot, and FISH analyses were consistent with the de novo deletion of one allele of SCO2 in the patient. This is the first report of hemizygosity in a SCO2 patient. The patient phenotype underscores the strikingly similar clinical course in all patients with one copy of the E140K allele. Examination of both patient and parental genotypes by thorough molecular analyses can reveal information with important implications for genetic counseling.
SCO2是一种参与线粒体铜传递的金属伴侣蛋白，其突变与早发性致命肥厚型心肌病相关。所有报道的患者至少携带一份常见的1541G>A（E140K）突变。携带一份E140K等位基因且伴有更有害突变的患者临床病程严重，而E140K突变纯合子患者发病较晚，生存期更长。在此，我们研究了一名患者，基于PCR产物的DNA测序和限制性内切酶分析，该患者似乎是常见的1541G>A突变的纯合子，但却表现为早发性严重心肌病。对其父母的DNA进行限制性内切酶分析发现，母亲是1541G>A的杂合子，而父亲是野生型纯合子。该患者在跨越22号染色体全长的微卫星标记上表现出双亲遗传，排除了单亲二体的可能性。对SCO2基因5'-UTR、内含子和单外显子内的几个单核苷酸多态性进行测序未提供有价值信息；然而，该患者和母亲的内含子中存在一个16 bp的缺失，父亲则没有。限制性内切酶分析证实母亲是该缺失的杂合子，患者是半合子。Southern印迹、Northern印迹和FISH分析均与该患者SCO2一个等位基因的新发缺失一致。这是SCO2患者半合子状态的首例报道。该患者的表型突出了所有携带一份E140K等位基因患者显著相似的临床病程。通过全面的分子分析检查患者及其父母的基因型，可为遗传咨询提供具有重要意义的信息。
