Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia

Ariana Kariminejad, Emmanuelle Szenker-Ravi, Caroline Lekszas, Homa Tajsharghi, Ali Reza Moslemi, Thomas Naert, Hong Thi Tran, Fatemeh Ahangari, Minoo Rajaei, Mojila Nasseri, Thomas Haaf, Afrooz Azad, Andrea Superti-Furga, Reza Maroofian, Siavash Ghaderi-Sohi, Hossein Najmabadi, Mohammad Reza Abbaszadegan, Kris Vleminckx, Pooneh Nikuei, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.
Original languageEnglish (US)
Pages (from-to)1294-1301
Number of pages8
JournalAmerican Journal of Human Genetics
Volume105
Issue number6
DOIs
StatePublished - Dec 5 2019
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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