FOXP2 gene is thought to be required for proper development of speech & language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways & cascades that may ultimately influence language development

1. FOXP2 gene Involvement in Speech
and Language Disorders
“Genes Involved in Speech and Language Disorders”
Chapter of the review of the current M.D. thesis: Clinical and Molecular Genetic Studies of Specific Language Impairment
Supervised by
Prof. Dr./ Alia Mahmoud El Shoubary
Professor of Phoniatrics - Faculty of Medicine, Ain Shams University
Prof. Dr. Samira Ismail Ibrahim
Professor of Clinical Genetics National Research Centre
Prof. Dr. Mona Lotfy Eissawi
Professor of Molecular Genetics National Research Centre
Dr. Ahmed Nabil Khattab
Lecturer of Phoniatrics - Faculty of Medicine Ain Shams University
Faculty of Medicine
Ain Shams University
Cairo
2016

2. Introduction
• The genetic mechanisms underlying
susceptibility to speech and language
disorders are multifactorial in nature
(involving complex interactions between several
genetic variants and environmental factors).
• Despite this complexity, researchers have
recently begun to identify genetic factors
that may play a role in the etiology of
speech and language disorders (Newbury et al., 2009 &
Kang et al., 2010).

3. Discovery of FOXP2 as a ‘Language Gene’
• Twin studies have shown that genetic factors play
an important role in the etiology of speech &
language disorders.
• However, a gene that predisposes individuals to
such disorders had not been identified until
FOXP2 gene was discovered in a large
three-generation family (called the KE family) (Fisher
et al., 1998).
• Half of the KE family members had an autosomal
dominant severe speech & language disorder (in
the form of severe orofacial & verbal dyspraxia, extreme
impairments in both expressive & receptive language skills as well
as non-verbal deficits & written language problems in some
individuals).

4. Discovery of FOXP2 as a ‘Language Gene’
• fMRI analysis of these individuals showed under-
activation of Broca’s area and the putamen, brain
centers thought to be involved in language.
• The gene locus in this family was mapped to the long
arm of chromosome 7 with strong evidence for linkage
to the region of 7q31 (Fisher et al., 1998).
• Mutations of this gene was found only in the affected
members of the KE family (with no mutations in the
unaffected members of this family or controls).

5. Discovery of FOXP2 as a ‘Language Gene’
• There was a child (referred to as “CS”) affected by
a severe orofacial dyspraxia and language deficits
similar to those seen in the KE family, with a de
novo mutation mapping to the same gene locus in
KE family (Lai et al., 2001).
• Accordingly, the gene mutated in the KE family
was identified as FOXP2 gene.
• FOXP2 gene is thought to be required for proper
development of speech & language regions of
the brain during embryogenesis, and may be
involved in a variety of biological pathways &
cascades that may ultimately influence language
development.

6. Discovery of FOXP2 as a ‘Language Gene’
• The normal humans have 2 identical
FOXP2 genes, each formed of 2594
base pairs.
• This sequence of FOXP2 gene is
organized into 19 exons (coding sequences of DNA)
which usually encodes a 715-residue
(amino acid) protein (FOXP2 protein).

7. Discovery of FOXP2 as a ‘Language Gene’
• The mutation identified in the KE family
is a G→A transition in exon 14 of FOXP2
gene.
• This one point mutation in the FOXP2
gene of the affected members of the KE
family is predicted to result in an
arginine to histidine substitution
(R553H) in the forkhead domain of the
FOXP2 resulting protein (missense mutation).

8. Discovery of FOXP2 as a ‘Language Gene’
• It is likely that the amino acid substitution in
FOXP2 protein leads to a loss of function of one
copy of the FOXP2 gene and that the remaining
copy is insufficient for FOXP2 function (haplo-
insufficiency).
• The KE and CS phenotypes may be caused by
that haplo-insufficiency of FOXP2 at a key stage
of embryogenesis which results in the abnormal
development of neural structures important for
speech and language.

9. Discovery of FOXP2 as a ‘Language Gene’
• FOXP2 gene is an important member of
the FOXP genes subfamily, which
constitutes in turn a part of a larger
family of genes, called FOX family.

10. The FOX Family:
• The FOX genes encode a large
family of transcription factors
(proteins), all of which possess
a winged-helix—or forkhead
box (“fox”)—DNA-binding
domain.
• These transcription factors may
bind directly to approximately
300 to 400 gene promoters in
the human genome to regulate
the expression of a variety of
genes.
• Many of these genes
functionally represent good
candidate genes for speech
and language disorders.

11. The FOXP Subfamily:
• The human FOX gene family consists of over 40
members, classified into 19 subfamilies
(designated FOXA to FOXS) according to
specific motifs within the DNA binding domain.
• The FOXP subfamily, which consists of four
members, FOXP1, FOXP2, FOXP3 and FOXP4, is
characterized on the basis of its members
containing a C2H2 type zinc finger domain, and a leucine
zipper motif, in addition to the fork head domain at the C
terminus.

12. The FOXP Subfamily:
• Members of the FOX family of proteins have
been demonstrated to bind to target DNA as
monomers.
• By contrast, The FOXP subfamily including
FOXP1, FOXP2 and FOXP4 proteins are found to
bind to each other to form heterodimers or
homodimers.
• This dimerization is required for DNA binding
capacity of these proteins & their transcriptional
activities.

13. The FOXP Subfamily:
• The precise combination of homodimers
and heterodimers of different FOXP
proteins in the same neurons may regulate
the transcription of downstream target
genes during brain development and, thus
control the patterning of brain structures
(Takahashi et al., 2009).

14. The FOXP Subfamily:
• Homodimers of FOXP2 proteins

15. The FOXP Subfamily:
• FOXP1, FOXP2 and FOXP4 are expressed in
the brain, and other organs, including the
lung, heart and gut, whereas FOXP3 is
exclusively expressed in the immune
system.
• FOXP2 is expressed in several structures of
the central nervous system during
development, including the cerebral
cortex, striatum, thalamus, cerebellum and
spinal cord.

16. The FOXP Subfamily:
• FOXP2 is extensively expressed in the
developing brain and its expression is
down regulated in the adult.
• There are many overlaps between the
expression patterns of FOXP2 and those of
its paralogs FOXP1 and FOXP4, although
detailed analysis revealed a distinct
pattern of expression for each member in
some neuronal cell types.

17. Wild-type FOXP2 protein versus mutant forms:
• The wild-type FOXP2 protein is the healthy
form, while the well-known mutant forms are
the ones resulting from R553H and R328X
mutations.
• R553H is missense mutation yielding
substitution of one amino acid with change of
the resulting FOXP2 protein.
• R328X is nonsense mutation yielding premature
stop codon resulting in incomplete (truncated)
unstable protein product.

18. Wild-type FOXP2 protein versus mutant forms:
1) Wild-type FOXP2 protein is localized mainly in
the nucleus, while this intracellular localization
is disrupted in the mutants: FOXP2 with a
R553H mutation is localized in both nucleus &
cytoplasm, whereas FOXP2 with R328X localized
predominantly in the cytoplasm.
2) Wild-type FOXP2 protein possesses DNA binding
capacity, while neither R553H nor R328X
mutants bound to the target DNA .
3) Wild type FOXP2, FOXP1 and FOXP4 function as
transcriptional repressor (for SV40 promoter),
whereas R528H and R328X mutants lose the
repressor activity.

19. Wild-type FOXP2 protein versus mutant forms:
• A fluorescent protein from jellyfish was fused to normal FOXP2 protein (on the left) and to a variant
FOXP2 protein from a child with language difficulties (on the right), and the protein was observed
inside human cells. The FOXP2 variant from the child with language difficulties clearly shows an
abnormal distribution within the cells, suggesting that this FOXP2 variant is the major cause of the
child's language problems. In this way, molecular studies can help provide a diagnosis in cases of
unexplained language difficulty.

20. FOXP2 in relation to language-related
disorders & speech disorders:
• Regarding SLI, Chromosome 7q31, in which
FOXP2 gene is located, has been implicated in
SLI.
• Although later studies showed no mutations in
exon 14 of the FOXP2 gene (where the KE family
mutation exists), a strong association to genetic
markers adjacent to FOXP2 was found,
suggesting that the genetic factors for regulation
of common language impairments (like SLI)
reside in the vicinity of FOXP2.

21. FOXP2 in relation to language-related
disorders & speech disorders:
• Chromosome 7q31 has been repeatedly linked
to autism, suggesting that this chromosomal
region is likely to harbor a susceptibility gene for
autism, raising the question of whether a single
gene on 7q might be involved in both autism
and SLI.
• However, the results of the majority of
association studies of FOXP2 and autism have
been negative, apart from two genetic
association studies in Japanese and Chinese
subjects which showed a positive association
(Gong et al., 2004 & Li et al., 2005).

22. FOXP2 in relation to language-related
disorders & speech disorders:
• Regarding dyslexia, association
analyses revealed a marginal level
of association between FOXP2
and reading, language, and
articulation supporting the
etiological relationships between
dyslexia and speech and
language disorders (Rice et al., 2009).

23. FOXP2 in relation to language-related
disorders & speech disorders:
• Regarding verbal dyspraxia, it seems
obvious that FOXP2 is important in the
etiology of severe and rare forms of
verbal dyspraxia, as shown in the KE
family, suggesting that this gene is of
particular importance in the development
of brain regions responsible for fine
motor control (motor cortex, striatum, &
cerebellum), and that its disruption has
exceptionally severe consequences for the
development of speech.

24. FOXP2 in relation to language-related
disorders & speech disorders:
• However, FOXP2 seems to be not
involved in the development of
other speech disorders like familial
persistent developmental
stuttering, suggesting that the
genetic neuropathological origins
of stuttering differ from those of
verbal dyspraxia and SLI.

25. Conclusion
• Since FOXP2 is a transcription factor, it
regulates the expression of other genes,
some of which may be expected to be
involved in more common forms of speech
and language deficits.
• FOXP2 protein bound to the promoters of
genes (target genes) involved in diverse
biological functions, including synaptic
transmission, neural development, cell
signaling, ion transport and axon guidance in
fetal human brain cell lines.

26. Conclusion
• The identification of FOXP2 gene heralded a
new era for the genetic study of speech and
language as it allows the identification of
some of the biological pathways and
neurological mechanisms important for
speech and language acquisition processes,
and play a critical role in the etiology of
speech & language disorders.