Solution structure and backbone dynamics of the DNA‐binding domain of FOXP1: Insight into its domain swapping and DNA binding

Chu, Yu-De; Chang, Chia Hao; Shiu, Jia Hau; Chang, Yao; Chen, Chiu Yueh; Chuang, Woei Jer

doi:10.1002/pro.626

Cited by 43 publications

(66 citation statements)

References 70 publications

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“…The identified hotspot was located in the third α -helix (H3), which exhibits a high degree of sequence homology across Fox proteins and binds to the major groove of DNA targets. Specifically, the arginine residue that we found mutated forms direct hydrogen bonding with DNA in both in FOXP and FOXK family transcription factors (Wu et al, 2006; Stroud et al, 2006; Chu et al, 2011) (Tsai et al, 2006) ( Fig. 5C, D ).…”

Section: Resultsmentioning

confidence: 92%

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains

et al. 2015

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SUMMARY In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots; identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene; detect previously unknown mutation hotspots; and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype.

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Section: Resultsmentioning

confidence: 92%

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains

et al. 2015

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“…Note that R525 resides in a β‐pleated sheet. The diagram was derived from the solution NMR structure deposited in the Molecular Modeling Database (MMDB ID: 81461) and Protein Databank (PDB ID: 2KIU) (PDB ID: 2KIU; MMDB ID: 81461) (Chu et al, ). [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Resultsmentioning

confidence: 99%

“…This variant, which has not been observed in the ExAC or ESP6500 databases, is predicted to encode the missense mutation p.R525Q, which alters a conserved amino acid within the S1 beta‐pleated sheet of the FOX domain (Figure c–e). This amino acid is involved in DNA binding (Chu et al, ; Stroud et al, ), and mutation of the homologous amino acid in FOXP3 (R397W) causes X‐linked neonatal diabetes mellitus, enteropathy, and endocrinopathy syndrome (Wildin et al, ).…”

Section: Resultsmentioning

confidence: 99%

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

Myers

Souich

Yang

et al. 2017

American J of Med Genetics Pt A

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The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.

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“…The average three-dimensional structure of the FOXP1 DNA binding domain was extracted from PDB #2KIU, which contains 20 NMR structures [ 37 ], and then superimposed to the FOXP2 domain co-crystallized with one double-stranded DNA molecule (PDB #2AO7) [ 38 ]. We mapped all missense and in-frame mutations from this and prior studies on to this structure.…”

Section: Methodsmentioning

confidence: 99%

Prospective investigation of FOXP1 syndrome

et al. 2017

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BackgroundHaploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments.MethodsGenetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1.ResultsWe have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections.ConclusionsThis study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.Electronic supplementary materialThe online ver...

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Solution structure and backbone dynamics of the DNA‐binding domain of FOXP1: Insight into its domain swapping and DNA binding

Cited by 43 publications

References 70 publications

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

Prospective investigation of FOXP1 syndrome

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