Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1

Tyler B Johnson,Jill M Weimer,Hailey Pinz,Mark A Wilson,Keegan Mechels,Megan Landsverk,Stephen Braddock,Kyle J Roux,Jacob T Cain,Ruthellen H Anderson,David A Sturdevant

doi:10.1038/s41598-018-34437-0

Abstract

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization.

Highlights

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features
The first patient reported to have a de novo c.1574G>A (p.R525Q) mutation in FOXP1 was previously described in two separate reports[1,39]
Shared among the patients harboring heterozygous mutations in FOXP1 are conditions including intellectual disability, language impairment, autistic features, motor coordination and dysmorphic features occasionally presenting with various cancers, and congenital defects of the heart, kidneys and urinary tract[1,2]

Summary

Introduction

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. We present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. Members of the FOXP subfamily, which includes four paralogous proteins, have crucial roles in embryonic development and organogenesis of heart, lung, esophagus, and immune system[3,4,5,6,7,8]. Each of these proteins share four common domains: an N-terminal Q-rich (polyglutamine) domain, internal zinc-finger and leucine zipper, and a C-terminal forkhead box DNA-binding domain (FOX). Foxp[1] plays an important role in cardiac development as Foxp[1] null mice are embryonic lethal due to defects in myocyte maturation leading to thinning of the ventricular myocardial compact zone[7]

Methods

Results

Conclusion