Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

Abstract

The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C4G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.

The contribution of platelet studies to the understanding of disease mechanisms in complex and monogenetic neurological disorders

“…No increased clinical bleeding tendency has been reported in these patients, but it was recently shown that platelets from these patients have decreased responses to epinephrine and abnormal granules. 77 These data suggest a non-transcriptional role of FOXG1 in the amplification of intracellular signal transduction after initial platelet activation.…”

“…76 Genes for some transcription factors, such as the forkhead box G1 (FOXG1) gene, are expressed in both platelets and neurons. 77 FOXG1 encodes a transcriptional repressor that is important for prenatal development of the ventral telencephalon by integrating several brain signalling centres. 78 Postnatally, FOXG1 promotes postmitotic neuronal cell survival.…”

Structural variation in the 3D genome

“…e | Balanced translocations at the MEF2C locus cause a regulator loss of function and are associated with anomalies of the brain (including callosum hypoplasia 142 ) and developmental delay 116 . For examples see REFS 99,104,143 . PRS, element associated with Pierre Robin sequence; RevSex, element associated with disorders of sex development.…”

Phenotypic interpretation of complex chromosomal rearrangements informed by nucleotide-level resolution and structural organization of chromatin

“…Of particular interest was the breakpoint located in 14q12, which fell amidst other rearrangement positions in association with RTT-like phenotypes and reportedly affecting FOXG1 function (Fig. 3) [4,[22][23][24]54]. Exome analysis by the DDD project ruled out the contribution of variants in known RTT genes (including methyl-CpG binding protein 2 (MECP2)) leading to the As demonstrated in other studies [4,[16][17][18][19][20]55], TAD disruption may affect expression of genes located within the domain by disrupting long-range promoter/enhancer interactions.…”