Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Fischer-Zirnsak, Björn; Segebrecht, Lara; Schubach, Max; Charles, Perrine; Alderman, Emily; Brown, Kathleen; Cadieux-Dion, Maxime; Cartwright, Tracy; Chen, Yanmin; Costin, Carrie; Fehr, Sarah; Fitzgerald, Keely; Fleming, Emily; Foss, Kimberly; Ha, Thoa K.; Hildebrand, Gabriele; Horn, Denise; Liu, Shuxi; Marco, Elysa J.; McDonald, Marie; McWalter, Kirsty; Race, Simone; Rush, Eric T.; Si, Yue; Saunders, Carol J.; Slavotinek, Anne; Stöckler‐Ipsiroglu, Sylvia; Telegrafi, Aida; Thiffault, Isabelle; Torti, Erin; Tsai, Anne Chun-Hui; Wang, Xin; Zafar, Muhammad Sohail; Keren, Boris; Kornak, Uwe; Boerkoel, Cornelius F.; Mirzaa, Ghayda; Ehmke, Nadja

doi:10.1016/j.ajhg.2019.07.002

Cited by 51 publications

(45 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This agrees with the recent identification of neurodevelopmental disorders apparently not typical to HPE but associated to haploinsufficiency of DLL1. In these patients, intellectual disability and variable brain malformations such as microcephaly occurs (66).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Hamdi-Rozé

Ware

Guyodo

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

View full text Add to dashboard Cite

Context In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown. Objective The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain. Design In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients. Results We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways. Conclusions These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.

show abstract

Section: Accepted Manuscriptmentioning

confidence: 99%

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Hamdi-Rozé

Ware

Guyodo

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

View full text Add to dashboard Cite

show abstract

“…The TBXT gene encodes for T protein, which is crucial for neurulation during embryonic development [ 14 ]. Additionally, the DLL1 gene encodes a Notch ligand protein which is necessary for the Notch signaling cascade involved in neuronal differentiation and migration during the embryonic period [ 15 ]. Haploinsufficiency of one or both of these genes may have resulted in our patient's seizures, structural brain/spine abnormalities, and intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

An Adolescent with a Rare De Novo Distal Trisomy 6p and Distal Monosomy 6q Chromosomal Combination

Peterman

Vance

Conboy

et al. 2020

Case Reports in Genetics

View full text Add to dashboard Cite

We report on a 12-year-old female with both a partial duplication and deletion involving chromosome 6. The duplication involves 6p25.3p24.3 (7.585 Mb) while the deletion includes 6q27q27 (6.244 Mb). This chromosomal abnormality is also described as distal trisomy 6p and distal monosomy 6q. The patient has a Chiari II malformation, hydrocephalus, agenesis of the corpus callosum, microcephaly, bilateral renal duplicated collecting system, scoliosis, and myelomeningocele associated with a neurogenic bladder and bladder reflux. Additional features have included seizures, feeding dysfunction, failure to thrive, sleep apnea, global developmental delay, intellectual disability, and absent speech. To our knowledge, our report is just the sixth case in the literature with concomitant distal 6p duplication and distal 6q deletion. Although a majority of chromosomal duplication-deletion cases have resulted from a parental pericentric inversion, the parents of our case have normal chromosomes. This is the first reported de novo case of distal 6p duplication and distal 6q deletion. Alternate explanations for the origin of the patient’s chromosome abnormalities include parental gonadal mosaicism, nonallelic homologous recombination, or potentially intrachromosomal transposition of the telomeres of chromosome 6. Nonpaternity was considered but ruled out by whole exome sequencing analysis.

show abstract

“…It was also demonstrated that two essential effectors of the Notch signaling are crucial for maintaining the embryonic nervous system structure, keeping the organization and morphology of the cells [ 62 ]. Additionally, pathogenic variants of the Notch ligand Dll1 have recently been suggested as causative of a neurodevelopmental phenotype in a cohort whose individuals presented with developmental delay, intellectual disability, and brain malformations [ 63 ].…”

Section: Lncrnas and Pathways Involved In Non-syndromic Intellectumentioning

confidence: 99%

Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective

Barros

Leão

Santis

et al. 2021

ncRNA

View full text Add to dashboard Cite

Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder.

show abstract

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Cited by 51 publications

References 49 publications

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

An Adolescent with a Rare De Novo Distal Trisomy 6p and Distal Monosomy 6q Chromosomal Combination

Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective

Contact Info

Product

Resources

About