Slavotinek, Anne and Risolino, Maurizio and Losa, Marta and Cho, Megan T and Monaghan, Kristin G. and Schneidman-Duhovny, Dina and Parisotto, Sarah and Herkert, Johanna C and Stegmann, Alexander P.A. and Miller, Kathryn and Shur, Natasha and Chui, Jacqueline and Muller, Eric and DeBrosse, Suzanne and Szot, Justin O and Chapman, Gavin and Pachter, Nicholas S and Winlaw, David S and Mendelsohn, Bryce A. and Dalton, Joline and Sarafoglou, Kyriakie and Karachunski, Peter I. and Lewis, Jane M and Pedro, Helio and Dunwoodie, Sally L and Selleri, Licia and Shieh, Joseph (2017) De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects. Human Molecular Genetics, 26 (24). pp.4849-4860. ISSN 0964-6906 (Not OA)
Slavotinek, Anne and Risolino, Maurizio and Losa, Marta and Cho, Megan T and Monaghan, Kristin G. and Schneidman-Duhovny, Dina and Parisotto, Sarah and Herkert, Johanna C and Stegmann, Alexander P.A. and Miller, Kathryn and Shur, Natasha and Chui, Jacqueline and Muller, Eric and DeBrosse, Suzanne and Szot, Justin O and Chapman, Gavin and Pachter, Nicholas S and Winlaw, David S and Mendelsohn, Bryce A. and Dalton, Joline and Sarafoglou, Kyriakie and Karachunski, Peter I. and Lewis, Jane M and Pedro, Helio and Dunwoodie, Sally L and Selleri, Licia and Shieh, Joseph (2017) De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects. Human Molecular Genetics, 26 (24). pp.4849-4860. ISSN 0964-6906 (Not OA)
Slavotinek, Anne and Risolino, Maurizio and Losa, Marta and Cho, Megan T and Monaghan, Kristin G. and Schneidman-Duhovny, Dina and Parisotto, Sarah and Herkert, Johanna C and Stegmann, Alexander P.A. and Miller, Kathryn and Shur, Natasha and Chui, Jacqueline and Muller, Eric and DeBrosse, Suzanne and Szot, Justin O and Chapman, Gavin and Pachter, Nicholas S and Winlaw, David S and Mendelsohn, Bryce A. and Dalton, Joline and Sarafoglou, Kyriakie and Karachunski, Peter I. and Lewis, Jane M and Pedro, Helio and Dunwoodie, Sally L and Selleri, Licia and Shieh, Joseph (2017) De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects. Human Molecular Genetics, 26 (24). pp.4849-4860. ISSN 0964-6906 (Not OA)
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.
Metadata
Subjects: | R Medicine > R Medicine (General) |
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Depositing User: | Repository Administrator |
Date Deposited: | 22 Oct 2017 22:46 |
Last Modified: | 20 Aug 2018 01:38 |