AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome

Abstract

Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation–migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.

SMCHD1 genetic variants in type 2 FacioScapuloHumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.

“…The pleiotropic impact of SMCHD1 variants or haploinsu ciency remains a key question to understand how variants in the same gene might lead to at least four different syndromes, 4,15,[17][18][19] in which D4Z4 hypomethylation but also DUX4 expression are consistently observed 17,18,35,[41][42][43] . In FSHD2, SMCHD1 variants were previously located around the ATP binding site or on a loop adjacent to the ATP binding pocket 23 .…”

DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose

“…In contrast, and despite D4Z4 hypomethylation in SMCHD1 KO NCC, DUX4 was not induced in SMCHD1 KO NCC. Notably, a recent study of NCC derived from one arhinia patient iPSC and one control iPSC also failed to demonstrate DUX4 induction in arhinia NCC but suggested that there may be a very mild defect in arhinia NCC migration related to diminished AKT signaling ( 46 ). Thus, while the primary defect in arhinia appears to be placodal, placode cell death may impair the proliferation and/or migration of nearby NCC such that a combined defect prevents the development of the human nose.…”

HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring

“…Gene Set Enrichment Analysis (GSEA) was performed on all genes expressed. RNA seq methods in primary fibroblast are described in Laberthionniere et al 38 .…”