The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

中文翻译：

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纯合子空TBX4突变导致骨盆后和肺发育不全的后遗症。

四足动物中后肢的发育特别依赖于转录因子TBX4。在人类中，由于单倍体功能不全，杂合性功能丧失的TBX4突变会导致显性小骨综合征（SPS）。在这里，我们表征了四名胎儿的惊人临床特征，这些胎儿具有骨盆和肺发育不全（PAPPA）的完全后眼后突。通过外显子组测序，我们发现PAPPA综合征是由人类胚胎发生期间纯合的TBX4失活突变引起的。在两个近亲的夫妇中，我们发现了一个纯合子胎儿中，不同的种系TBX4编码突变p.Tyr113 *和p.Tyr127Asn与杂合子父母中的SPS和骨盆和肺发育不全综合征（PAPPAS）的后方眼病分离。在该先证者中，双等位基因p完全不存在TBX4转录本。Tyr113 *终止增益突变显示无义介导的内源性mRNA衰减。爪蟾胚胎中的CRISPR / Cas9介导的TBX4缺失证实了其在腿发育过程中的限制性作用。我们得出的结论是，SPS和PAPPAS是TBX4缺乏症的等位基因疾病，并且TBX4是人类肺部，骨盆和后肢器官发生的重要转录因子。