Lacombe Arnaud, Lee Hane, Zahed Laila, Choucair Mahmoud, Muller Jean-Marc, Nelson Stanley F, Salameh Wael, Vilain Eric
Department of Human Genetics, University of California at Los Angeles, 90095, USA.
Am J Hum Genet. 2006 Jul;79(1):113-9. doi: 10.1086/505406. Epub 2006 May 26.
Premature ovarian failure (POF) is characterized by elevated gonadotropins and amenorrhea in women aged <40 years. In a Lebanese family with five sisters who received the diagnosis of POF, we established linkage to the long arm of the X chromosome (between Xq21.1 and Xq21.3.3), using whole-genome SNP typing and homozygosity-by-descent mapping. By sequencing one candidate gene within that region, POF1B, we identified a point mutation localized in exon 10. This substitution of a nucleotide (G-->A), at position 1123, results in an arginine-->glutamine mutation of the protein sequence at position 329 (mutation R329Q). All the affected family members were homozygous for the mutation, whereas the unaffected members were heterozygous. Because POF1B shares high homology with the tail portion of the human myosin, we assessed the ability of both wild-type and mutant POF1B proteins to bind nonmuscle actin filaments in vitro. We found that the capacity of the mutant protein to bind nonmuscle actin filaments was diminished fourfold compared with the wild type, suggesting a function of POF1B in germ-cell division. Our study suggests that a homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments.
卵巢早衰（POF）的特征是40岁以下女性促性腺激素升高和闭经。在一个有五姐妹被诊断为POF的黎巴嫩家庭中，我们利用全基因组SNP分型和基于家系的纯合性定位，将其与X染色体长臂（Xq21.1和Xq21.3.3之间）建立了连锁关系。通过对该区域内的一个候选基因POF1B进行测序，我们在第10外显子中发现了一个点突变。该核苷酸在第1123位的替换（G→A）导致蛋白质序列第329位的精氨酸→谷氨酰胺突变（R329Q突变）。所有受影响的家庭成员均为该突变的纯合子，而未受影响的成员为杂合子。由于POF1B与人类肌球蛋白的尾部具有高度同源性，我们评估了野生型和突变型POF1B蛋白在体外结合非肌肉肌动蛋白丝的能力。我们发现，与野生型相比，突变蛋白结合非肌肉肌动蛋白丝的能力降低了四倍，这表明POF1B在生殖细胞分裂中具有一定功能。我们的研究表明，POF1B中的纯合点突变通过改变POF1B与非肌肉肌动蛋白丝的结合来影响POF的发病机制。
