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

Am J Hum Genet. 2019 Dec 5;105(6):1294-1301. doi: 10.1016/j.ajhg.2019.10.013.

Ariana Kariminejad ¹, Emmanuelle Szenker-Ravi ², Caroline Lekszas ³, Homa Tajsharghi ⁴, Ali-Reza Moslemi ⁵, Thomas Naert ⁶, Hong Thi Tran ⁶, Fatemeh Ahangari ¹, Minoo Rajaei ⁷, Mojila Nasseri ⁸, Thomas Haaf ³, Afrooz Azad ⁷, Andrea Superti-Furga ⁹, Reza Maroofian ¹⁰, Siavash Ghaderi-Sohi ¹, Hossein Najmabadi ¹¹, Mohammad Reza Abbaszadegan ¹², Kris Vleminckx ⁶, Pooneh Nikuei ¹³, Bruno Reversade ¹⁴

Affiliations

1 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14665, Iran.
2 Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, Singapore 138648, Republic of Singapore.
3 Institute of Human Genetics, Julius-Maximilians-Universität, 97074 Würzburg, Germany.
4 School of Health Sciences, Division Biomedicine, University of Skövde, 54128 Skövde, Sweden.
5 Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, 41390 Gothenburg, Sweden.
6 Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
7 Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran.
8 Pardis Clinical and Genetics Laboratory, Mashhad 9177948974, Iran.
9 Division of Genetic Medicine, Lausanne University Hospital (CHUV), University of Lausanne, 1011 Lausanne, Switzerland.
10 Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
11 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14665, Iran; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran.
12 Pardis Clinical and Genetics Laboratory, Mashhad 9177948974, Iran; Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad 15731, Iran.
13 Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran. Electronic address: poonehnikuei@gmail.com.
14 Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, Singapore 138648, Republic of Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Department of Medical Genetics, Koç University, School of Medicine, 34010 Topkapı, Istanbul, Turkey. Electronic address: bruno@reversade.com.

PMID: 31761294 DOI: 10.1016/j.ajhg.2019.10.013

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.

Keywords

PAPPAS; SPS; TBX4; Xenopus; allelic diseases; animal models; hindlimb amelia; lung and pelvis hypoplasia; semi-dominant; small patella syndrome.

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