Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Hum Mol Genet. 2017 Dec 15;26(24):4849-4860. doi: 10.1093/hmg/ddx363.
We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs2, and p.Arg288 yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.
我们介绍了 8 例 PBX1 基因中新出现的、有害的序列变异患者。PBX1 编码一个三氨基酸环延伸（TALE）同源结构域转录因子，它与 TALE 和 HOX 蛋白形成多聚体复合物，在发育过程中调节靶基因转录。如前所述，Pbx1 纯合突变小鼠（Pbx1-/-）表现出多种器官的畸形和发育不良或发育不全，包括颅面骨骼、耳朵、鳃弓、心脏、肺、膈、肠道、肾脏和性腺。所有患者均表现出与 Pbx 突变小鼠相似的临床表现，表现出不同的外显率和严重程度，包括外耳畸形、鳃弓衍生结构异常、心脏畸形、膈疝、肾脏发育不全和生殖器模糊。除 1 例患者外，所有患者均存在发育迟缓。以前报道的影响肾脏和泌尿道的先天性异常患者，在 PBX1 中存在缺失和功能丧失变异。我们病例中的序列变异包括 PBX1 同源结构域附近的错义替换（p.Arg184Pro、p.Met224Lys 和 p.Arg227Pro）或同源结构域内的替换（p.Arg234Pro 和 p.Arg235Gln），而 p.Ser262Glnfs2 和 p.Arg288导致截短的 PBX1 蛋白。对 5 个 PBX1 序列变异的功能研究表明，其内在的 PBX 依赖性反式激活能力受到干扰，核易位改变，提示突变 PBX1 蛋白与野生型 TALE 或 HOX 辅助因子之间的异常相互作用。这些突变很可能直接影响 PBX1 靶基因的转录，从而影响胚胎发育。我们得出结论，PBX1 中的有害序列变异导致智力障碍和与 Pbx1 突变小鼠相似的多种畸形，这表明这两个物种之间基因功能的高度保守性。
