Biallelic loss of function of the promyelocytic leukaemia zinc finger (PLZF) gene causes severe skeletal defects and genital hypoplasia
Biallelic loss of function of the promyelocytic leukaemia zinc finger (PLZF) gene causes severe skeletal defects and genital hypoplasia
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DOI：
10.1136/jmg.2008.059451
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发表时间：
2008-11-01
影响因子：
4
通讯作者：
Wieczorek, D.
中科院分区：
文献类型：
--
作者：
Fischer, S.;Kohlhase, J.;Wieczorek, D.
背景：11q23 缺失与智力低下、颅面畸形、小头畸形和身材矮小有关。我们介绍了一名具有相似临床表现的患者，除了拇指缺失、桡骨和尺骨发育不全、额外的椎骨和肋骨、骨龄迟缓和生殖器发育不全之外。方法：通过基于阵列的比较基因组杂交，筛查患者的基因组 DNA 是否存在染色体失衡。为了识别候选基因突变，进行了 DNA 序列分析和报告基因检测。结果：患者在父系 11 号染色体上有类似 8 Mbp 的从头缺失，其中包括早幼粒细胞白血病锌指基因（PLZF、ZBTB16；OMIM 176797）。母体 PLZF 等位基因具有隐性错义突变 (c. 1849A-->G)，导致锌指基序内高度保守的蛋氨酸被缬氨酸 (p. Met617Val) 取代。考虑到 Val 和 Met 的特定 α 螺旋倾向，这种突变可能会破坏与 DNA 双链体形成接触的锌指的 α 螺旋的稳定性，从而影响报告基因检测显示的生物学功能。 讨论：PLZF 基因是急性早幼粒细胞白血病中与视黄酸受体 α 融合的五个伙伴之一。据我们所知，我们描述了第一位患有 PLZF 种系突变的患者。我们的研究结果以及对 PLZF 缺陷小鼠的观察表明，PLZF 是骨骼和雄性种系发育的关键调节因子。此外，该病例强调了在具有微缺失和非典型临床表现的患者的未缺失染色体上寻找隐性突变的重要性。
Background: Deletions of 11q23 are associated with mental retardation, craniofacial dysmorphism, microcephaly and short stature. We present a patient with similar clinical findings, in addition to absence of the thumbs, hypoplasia of the radii and ulnae, additional vertebrae and ribs, retarded bone age and genital hypoplasia.Methods: Genomic DNA from the patient was screened for chromosomal imbalances by array-based comparative genomic hybridisation. DNA sequence analyses and reporter gene assays were performed in order to identify candidate gene mutations.Results: The patient has an similar to 8 Mbp de novo deletion on the paternal chromosome 11, which includes the promyelocytic leukaemia zinc-finger gene (PLZF, ZBTB16; OMIM 176797). The maternal PLZF allele harbours a recessive missense mutation (c. 1849A-->G), which leads to the substitution of a highly conserved methionine by valine (p. Met617Val) within a zinc-finger motif. Taking into account specific alpha-helical propensities of Val and Met, this mutation is likely to destabilise the alpha helix of the zinc finger that forms the contact with the DNA duplex, thus affecting the biological function as shown by reporter-gene assays.Discussion: The PLZF gene is one of five partners fused to the retinoic acid receptor alpha in acute promyelocytic leukaemia. We describe the first patient, to our knowledge, with a germline mutation of PLZF. Our findings as well as observations in Plzf-deficient mice indicate that PLZF is a key regulator of skeletal and male germline development. Furthermore, this case highlights the importance of searching for a recessive mutation on the non-deleted chromosome in patients with a microdeletion and atypical clinical findings.