De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects

Anne Slavotinek; Maurizio Risolino; Marta Losa; Megan T Cho; Kristin G Monaghan; Dina Schneidman-Duhovny; Sarah Parisotto; Johanna C Herkert; Alexander P A Stegmann; Kathryn Miller; Natasha Shur; Jacqueline Chui; Eric Muller; Suzanne DeBrosse; Justin O Szot; Gavin Chapman; Nicholas S Pachter; David S Winlaw; Bryce A Mendelsohn; Joline Dalton; Kyriakie Sarafoglou; Peter I Karachunski; Jane M Lewis; Helio Pedro; Sally L Dunwoodie; Licia Selleri; Joseph Shieh

doi:10.1093/hmg/ddx363

De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects

Hum Mol Genet. 2017 Dec 15;26(24):4849-4860. doi: 10.1093/hmg/ddx363.

Authors

Anne Slavotinek^{1

2}, Maurizio Risolino^{2

3}, Marta Losa^{2

3}, Megan T Cho⁴, Kristin G Monaghan⁴, Dina Schneidman-Duhovny^{5

6}, Sarah Parisotto⁷, Johanna C Herkert⁸, Alexander P A Stegmann^{9

10}, Kathryn Miller¹¹, Natasha Shur¹¹, Jacqueline Chui¹², Eric Muller¹², Suzanne DeBrosse¹³, Justin O Szot^{14

15}, Gavin Chapman^{14

15}, Nicholas S Pachter^{16

17}, David S Winlaw^{18

19}, Bryce A Mendelsohn^{1

2}, Joline Dalton²⁰, Kyriakie Sarafoglou²¹, Peter I Karachunski²², Jane M Lewis²³, Helio Pedro⁷, Sally L Dunwoodie^{14

15}, Licia Selleri^{2

3}, Joseph Shieh^{1

2}

Affiliations

¹ Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
² Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA.
³ Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, University of California San Francisco, San Francisco, CA, USA.
⁴ GeneDx, Gaithersburg, MD, USA.
⁵ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁶ Department of Biochemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁷ Division of Genetics, Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ, USA.
⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁰ Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
¹¹ Department of Pediatrics, Albany Medical Center, Albany, NY, USA.
¹² Clinical Genetics, Stanford Children's Health at CPMC, San Francisco, CA, USA.
¹³ Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
¹⁴ Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
¹⁵ University of New South Wales, Sydney, NSW, Australia.
¹⁶ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia.
¹⁷ School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
¹⁸ University of Sydney, Medical School, Sydney, NSW, Australia.
¹⁹ Heart Centre for Children, Children's Hospital at Westmead, Sydney, NSW, Australia.
²⁰ Paul and Shelia Wellstone Muscular Dystrophy Center, University of Minnesota, Minneapolis, MN, USA.
²¹ Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
²² Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
²³ Department of Urology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Abstract

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.Ser262Glnfs*2, 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.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Amino Acid Sequence
Animals
Child
Child, Preschool
Female
Genetic Pleiotropy / genetics
Homeodomain Proteins / genetics
Humans
Infant
Infant, Newborn
Intellectual Disability / genetics*
Male
Mice
Pre-B-Cell Leukemia Transcription Factor 1 / genetics*
Pre-B-Cell Leukemia Transcription Factor 1 / metabolism*
Pregnancy
Protein Binding
Proto-Oncogene Proteins / genetics
Transcription Factors / genetics

Substances

Homeodomain Proteins
Pre-B-Cell Leukemia Transcription Factor 1
Proto-Oncogene Proteins
Transcription Factors
PBX1 protein, human

Grants and funding

R01 DE024745/DE/NIDCR NIH HHS/United States