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Am J Hum Genet 2019 Dec 05;1056:1294-1301. doi: 10.1016/j.ajhg.2019.10.013.
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Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

Kariminejad A , Szenker-Ravi E , Lekszas C , Tajsharghi H , Moslemi AR , Naert T , Tran HT , Ahangari F , Rajaei M , Nasseri M , Haaf T , Azad A , Superti-Furga A , Maroofian R , Ghaderi-Sohi S , Najmabadi H , Abbaszadegan MR , Vleminckx K , Nikuei P , Reversade B .

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.

PubMed ID: 31761294
PMC ID: PMC6904794
Article link: Am J Hum Genet

Species referenced: Xenopus
Genes referenced: actb fgf10 hhip mmut rspo2 shox2 sms tbx3 tbx4 tbx5
gRNAs referenced: tbx4 gRNA1 tbx4 gRNA2

Disease Ontology terms: Holt-Oram syndrome [+]
Phenotypes: Xtr.wt +tbx4 CRISPR (Fig, S2.) [+]

Article Images: [+] show captions
References [+] :
Agarwal, Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. 2003, Pubmed