Faculty Collaboration Database

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology. Eur J Hum Genet 2023 Nov;31(11):1251-1260

Date

08/30/2023

Pubmed ID

37644171

Pubmed Central ID

PMC10620399

DOI

10.1038/s41431-023-01445-2

Scopus ID

2-s2.0-85168862554 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1^+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1^+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1^+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1^+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Author List

Oppermann H, Marcos-Grañeda E, Weiss LA, Gurnett CA, Jelsig AM, Vineke SH, Isidor B, Mercier S, Magnussen K, Zacher P, Hashim M, Pagnamenta AT, Race S, Srivastava S, Frazier Z, Maiwald R, Pergande M, Milani D, Rinelli M, Levy J, Krey I, Fontana P, Lonardo F, Riley S, Kretzer J, Rankin J, Reis LM, Semina EV, Reuter MS, Scherer SW, Iascone M, Weis D, Fagerberg CR, Brasch-Andersen C, Hansen LK, Kuechler A, Noble N, Gardham A, Tenney J, Rathore G, Beck-Woedl S, Haack TB, Pavlidou DC, Atallah I, Vodopiutz J, Janecke AR, Hsieh TC, Lesmann H, Klinkhammer H, Krawitz PM, Lemke JR, Jamra RA, Nieto M, Tümer Z, Platzer K

Author

Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Animals
Heterozygote
Homeodomain Proteins
Humans
Intellectual Disability
Mice
Neurodevelopmental Disorders
Phenotype
Repressor Proteins
Seizures
Transcription Factors