Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.
9 affiliations
- 1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, United States.
- 2Pediatric Surgical Research Laboratories, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114, United States.
- 3Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
- 4Department of Systems Biology, Columbia University Irving Medical Center, 622 West 168th Street New York, NY 10032, United States.
- 5Department of Surgery, Harvard Medical School, 25 Shattuck Street Boston, MA 02115, United States.
- 6Department of Surgery, Boston Children's Hospital, 300 Longwood Avenue Boston, MA 02115, United States.
- 7Department of Pediatrics, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114, United States.
- 8Department of Pediatrics, Harvard Medical School, 25 Shattuck Street Boston, MA 02115, United States.
- 9Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue Boston, MA 02115, United States.
Abstract
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly characterized by impairment of both diaphragm and lung development in utero. CDH presents as a spectrum of forms and severities, with diaphragm defects arising in the dorsal/posterior region typically correlating with more severe pulmonary disease and higher risk of mortality than those appearing in ventral/anterior regions. The genetic etiology underlying CDH is complex, with many implicated genes showing variable expressivity and incomplete penetrance in both human patients and mouse models. Here we present in vivo validation of two genes previously unassociated with CDH: the CDC42-interacting kinase CDC42BPB; and CNOT1, a scaffolding protein of the CCR4-NOT protein complex, critical for mRNA regulation through modifications such as deadenylation. Each gene was found to have a damaging, de novo missense variant in a recent large-scale CDH patient sequencing screen. Loss of Cdc42bpb leads to ventral diaphragmatic hernias, heart septal defects, and minor lung epithelial differentiation defects in mouse embryos. Installation of the orthologous patient-specific missense variant through CRISPR/Cas9 editing leads to less severe ventral diaphragm defects. Mouse embryos with either one or two copies of the orthologous Cnot1 variant, c.1867C > T (p.R623W), develop dorsal diaphragmatic hernias with low (<50%) penetrance, and mutants showed alterations in mRNA isoform expression consistent with the molecular role of Cnot1 in RNA splicing. These results underscore the power of in vivo functional modeling to validate genes and patient-specific variants uncovered by patient sequencing, reveal two previously unrecognized genetic causes of CDH, and highlight the heterogeneity of different patient anatomic presentations.
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BibTeX
@article{bogenschutz2026modeling,
title = {{Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.}},
author = {Eric L Bogenschutz and Cynthia Carpenter and Ameleen Wong and Kristina Palmer and Aalekh S Mehta and Yannick Ledermann and Caleb Heffner and Kathy J Snow and Carol Bult and Yufeng Shen and Patricia K Donahoe and Samuel P Rowbotham and Frances A High and Wendy K Chung and Stephen A Murray},
journal = {Human molecular genetics},
year = {2026},
month = oct,
doi = {10.1093/hmg/ddag106},
url = {https://europepmc.org/article/MED/42873655},
note = {CC BY},
}
RIS
TY - JOUR
TI - Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.
AU - Eric L Bogenschutz
AU - Cynthia Carpenter
AU - Ameleen Wong
AU - Kristina Palmer
AU - Aalekh S Mehta
AU - Yannick Ledermann
AU - Caleb Heffner
AU - Kathy J Snow
AU - Carol Bult
AU - Yufeng Shen
AU - Patricia K Donahoe
AU - Samuel P Rowbotham
AU - Frances A High
AU - Wendy K Chung
AU - Stephen A Murray
PY - 2026
DA - 2026/10/01
JO - Human molecular genetics
DO - 10.1093/hmg/ddag106
UR - https://europepmc.org/article/MED/42873655
AB - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly characterized by impairment of both diaphragm and lung development in utero. CDH presents as a spectrum of forms and severities, with diaphragm defects arising in the dorsal/posterior region typically correlating with more severe pulmonary disease and higher risk of mortality than those appearing in ventral/anterior regions. The genetic etiology underlying CDH is complex, with many implicated genes showing variable expressivity and incomplete penetrance in both human patients and mouse models. Here we present in vivo validation of two genes previously unassociated with CDH: the CDC42-interacting kinase CDC42BPB; and CNOT1, a scaffolding protein of the CCR4-NOT protein complex, critical for mRNA regulation through modifications such as deadenylation. Each gene was found to have a damaging, de novo missense variant in a recent large-scale CDH patient sequencing screen. Loss of Cdc42bpb leads to ventral diaphragmatic hernias, heart septal defects, and minor lung epithelial differentiation defects in mouse embryos. Installation of the orthologous patient-specific missense variant through CRISPR/Cas9 editing leads to less severe ventral diaphragm defects. Mouse embryos with either one or two copies of the orthologous Cnot1 variant, c.1867C > T (p.R623W), develop dorsal diaphragmatic hernias with low (<50%) penetrance, and mutants showed alterations in mRNA isoform expression consistent with the molecular role of Cnot1 in RNA splicing. These results underscore the power of in vivo functional modeling to validate genes and patient-specific variants uncovered by patient sequencing, reveal two previously unrecognized genetic causes of CDH, and highlight the heterogeneity of different patient anatomic presentations.
SN - 0964-6906
SN - 1460-2083
ER -