Introduction from (Pulido Fontes, Quesada Jimenez and Mendioroz Iriarte,

Introduction

 

 DNA methylation
is an example of epigenetic modification, used by cells to regulate gene
expression. DNA methylation is essential element in variety cellular processes,
involving x-chromosome inactivation, chromosome stability, genomic imprinting,
embryonic development, and gene suppression (Phillips, 2008). In
eukaryotes methyl (CH3) group is added directly to the carbon 5 of the cytosine
residue that exists in a cytosine-guanine (CpG) sequence. The distribution of
these molecules is in a random manner. They appear in bunches referred to as
CpG islands that positioned in gene promoters site. Methylation is accomplished
by DNA methyltransferases (DNMT). In mammals five DNA
methyltransferase have been determined, DNMT1, DNMT2, DNMT3L, DNMT3A, and
DNMT3B (Matarazzo et al., 2009). The methylation of CpG island in
promoter region is associated with gene silencing (transcription inhibition).

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Two basic mechanisms can be used by methylated CpG island for inhibits transcription
(Figure, 1). The first mechanisms occur when the transcription regulatory
factor binds to methylated CpG island. The second mechanism includes specific
protein complexes that recognized and bind to methylated CpG island and it
limits the access of regulatory molecules that blocks transcription factor from
binding to methylated CpG site. Protein complexes are referred to methyl CpG binding
domains (MBDs) and in mammals there are five families, MBD1,
MBD2, MBD3, and MBD4, MeCP2 (Pulido
Fontes, Quesada Jimenez and Mendioroz Iriarte, 2015). Error
in DNA methylation is related to human diseases. Both Rett syndrome and ICF
syndrome caused by defects related to DNA methylation machinery.

 

 

(Figure, 1) The image is adopted from
(Pulido Fontes, Quesada Jimenez and Mendioroz Iriarte, 2015).  Transcription process is stopped when CpG
island is methylated. Methylation inhibits transcription whether directly by
blocking transcription factor binding, or indirectly by binding MBD proteins to
methylated CpG island.

 

 

Another type of epigenetic modification is histone
modification where Acetyl or methyl group are directly added onto histone tails
and this modified gene expression. Histone modification has been studied on the
inactive X-chromosome in ICF and Rett syndrome cells. The results suggested
that inactive X-chromosome in ICF cells (hypomethylated) demonstrates normal
histone modification configurations (Gartler et al., 2004). Inactive
X-chromosome in Rett cells with a mutation in MeCP2 methyl-CpG binding protein
also demonstrates normal histone modification configurations (Gartler
et al., 2004). These results suggested that patterns of histone
modification are not identified by DNA methylation and methyl-CpG binding
protein on the inactive X-chromosome.      

 

 

 

 

ICF syndrome

 

The immunodeficiency, centromeric instability, and
facial anomalies (ICF) syndrome is an orphan
autosomal recessive disease, first described in 1978 (Sterlin
et al., 2016). The features of ICF syndrome includes facial dysmorphisms,
hypertelorism (large distance between eyes), macroglossia (large tongue), epicanthal
folds, low set ears, low serum immunoglobin, highly exposed to infection
diseases, flat nasal bridge, and it is distanced by multi-diverging of
juxtacentromeric sections of chromosome 1,9, and 16 after phytohemagglutinin
(PHA) stimulation of lymphocytes (OMIM #242860). Also they may suffer from
physical and mental impairment. It also characterized by the deficiency of
memory (CD19+ CD27+) B cells that situated in blood and changeable cellular
reduction (Sterlin et al., 2016). The change in
the position of chromosome structure is related to DNA hypomethylation in the
heterochromatin areas of Chr 1, 9 and 16 are a distinctive feature of this
disease (Sterlin et al., 2016). ICF syndrome is
associated with mutation in the DNA methyltransferase-3b (DNMT3B) gene,
deregulated of its activity cause hypomethylation, which result in heterochromatin,
and is related to chromosome instability and disabled chromosome segregation (Walton,
Francastel and Velasco, 2014).

 

 

The causes of ICF syndrome

 

ICF syndrome is heterogeneous disorder and caused by
germline gene mutations in DNMT3B gene (one of the DNA methyltransferase genes)
(Matarazzo et al., 2009). They were about 50-60% cases with mutations in DNMT3B
considered as ICF patients, not all patients with ICF had this mutation. DNMT3B
gene is plays a significant role in mammalian development and its dysfunction
is linked to several human diseases. DNMT3B gene is encodes for a protein that
binds to methylated DNA (Kaya et al., 2010). DNMT3B gene is located in 20q11.2,
this mutation is repeatedly found in C- terminal portion of protein, which
holds the catalytic domain (Matarazzo et al., 2009).  The majority of these mutations are missense;
others involve nonsense and splice site mutations (Matarazzo et al., 2009). About
1/3 ICF patients shows homozygous mutation, whereas the rest shows compound
heterozygous (Matarazzo et al., 2009). 

 

Also numbers of ICF syndrome patients (almost 30%) have been
identified with a mutation in zinc-finger and BTB domain-containing 24 (ZBTB24)
(Walton, Francastel and Velasco, 2014). This signifying that ICF type 2 is
caused by malfunctions of ZBTB24. ZBTB24 is a member of transcription factor
that plays a role in regulating lymphoid development and function (Walton,
Francastel and Velasco, 2014). It also involves in B cell distinction (Sterlin
et al., 2016). No sufficient information present about ZBTB24 at the main time,
but it has been limited to heterochromatin and it can be associated with
controlling extremely methylated areas (Sterlin et al., 2016). The most
distinguished signs in ICF2 individuals are mental disabilities, whereas the
lack of antibodies tends to be more common in ICF individuals (Sterlin et al.,
2016). Other cases of ICF patient have no indication of which mutation is
present ZBTB24 or DNMT3B and it is named ICFX. However, more recent studies
indicates that ICF type 3 and ICF type 4 patients have mutations in CDCA7 and
HELLS, highlighted the heterogeneity of the ICF syndrome (Sterlin et al.,
2016). 

 

Rett syndrome

 

Rett syndrome is a rare but severe x-linked
neurological disorder that primarily affecting girls. It occurs once every
10000-22000 live female births (Kriaucionis and Bird, 2003). The
signs of this disorder cannot be recognized during early development until
around 6-18 months followed by a skill regression that includes loss of
communication and motor skills, autism, seizures, stereotypic hand movements, microcephaly,
ataxia, irregular breathing patterns, spinal curvature, gastrointestinal
problems, and mental retardation (OMIM #312750). Rett syndrome is typically related
to serious intellectual and physical disability. The severity of the symptoms
differs among affected children. However, even with these symptoms, patients usually
survive into adulthood. Recent studies reported that the condition does not
engage progressive neurodegeneration as no further regression has been occurred
(Kriaucionis and Bird, 2003). Over time, girls
with Rett syndrome appear to improve in their communication skills. Rett
syndrome is caused by a single gene defects that causes of underproduction of important
brain proteins.

 

The causes of Rett syndrome

 

Rett syndrome is a genetic disease caused by a
mutation in methyl-CpG-binding protein 2 (MeCP2). Studies shows that, about 80%
of Rett syndrome cases are associated with a defect in MECP2 gene (Kriaucionis
and Bird, 2003) that is located on X-chromosome at position Xq28 (Figure, 2).

MECP2 gene is responsible for other genes function and also supplies
instructions for making MeCP2 protein that is essential for healthy brain
function. The accurate function of MeCP2 protein is still uncertain. However
the normal function of this protein is to regulate gene expression by modifying
chromatin. The defects on MECP2 gene is linked to several diseases. MeCP2
protein is required for brain development. This protein is a chromatin-associated
protein that can activate and repress transcription. The MECP2 mechanism that
causes Rett syndrome is not completely understood. However, the majority of
missense mutations in MECP2 are closely accumulated at methyl-CpG binding
domain (MBD) (Kriaucionis and Bird, 2003). The significance of MECP2
mutations in X-linked is uncertain due to insufficient mutation frequency and
rather the large capability of symptoms of Rett syndrome (Kriaucionis and Bird,
2003). The mutations in MECP2 gene change the formation of MeCP2 protein and
produced insufficient amount of the protein. The dysfunction of MeCP2 protein
disables the regulation of gene expression that requires by brain cells and it
might interrupt alternative splicing of proteins that are essential for the
interaction among neurons.

 

Rett syndrome is a rarely affects boy; boys who are affected
would not live for long (beyond 2 years) as they experience serious health problems
and their phenotype are more severe than Rett syndrome. And females are most
affected because MECP2 is X-linked and patients are heterozygous for the
mutated allele (Kriaucionis and Bird, 2003). 
Girls who are affected with MECP2 mutations, their half-cells express
wild type (wt) MECP2 and the other half express the defected MECP2. 

 

 

 

 

(Figure, 2) Adopted from Genetics Home Reference site.

 MECP2 gene is located in X-chromosome on
the long arm at position 28 as indicated by yellow arrow in the diagram.

 

 

 

 

Summary

 

DNA methylation
is important for gene expression, any mutation is related to serious human
diseases. ICF syndrome is resulted from several type of mutation; no
functioning link has been determined between these mutations. Four types of ICF
syndromes categorized because of different mutation caused, which includes DNMT3B,
ZBTB24, CDCA7, HELLS, hence it emphasized by its genetic heterogeneity. Rett
syndrome is caused by a mutation in MeCP2 protein, mostly affected girls and
rarely affects boys. However affected boys will die immediately after birth as
they had one copy of X-chromosome and they do not possess effective protection
system against infections. No cure is available for ICF syndrome and Rett
syndrome.