Introduction   DNA methylationis an example of epigenetic modification, used by cells to regulate geneexpression.

DNA methylation is essential element in variety cellular processes,involving x-chromosome inactivation, chromosome stability, genomic imprinting,embryonic development, and gene suppression (Phillips, 2008). Ineukaryotes methyl (CH3) group is added directly to the carbon 5 of the cytosineresidue that exists in a cytosine-guanine (CpG) sequence. The distribution ofthese molecules is in a random manner. They appear in bunches referred to asCpG islands that positioned in gene promoters site. Methylation is accomplishedby DNA methyltransferases (DNMT).

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In mammals five DNAmethyltransferase have been determined, DNMT1, DNMT2, DNMT3L, DNMT3A, andDNMT3B (Matarazzo et al., 2009). The methylation of CpG island inpromoter region is associated with gene silencing (transcription inhibition).Two basic mechanisms can be used by methylated CpG island for inhibits transcription(Figure, 1). The first mechanisms occur when the transcription regulatoryfactor binds to methylated CpG island. The second mechanism includes specificprotein complexes that recognized and bind to methylated CpG island and itlimits the access of regulatory molecules that blocks transcription factor frombinding to methylated CpG site. Protein complexes are referred to methyl CpG bindingdomains (MBDs) and in mammals there are five families, MBD1,MBD2, MBD3, and MBD4, MeCP2 (PulidoFontes, Quesada Jimenez and Mendioroz Iriarte, 2015). Errorin DNA methylation is related to human diseases.

Both Rett syndrome and ICFsyndrome 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 CpGisland is methylated. Methylation inhibits transcription whether directly byblocking transcription factor binding, or indirectly by binding MBD proteins tomethylated CpG island.   Another type of epigenetic modification is histonemodification where Acetyl or methyl group are directly added onto histone tailsand this modified gene expression. Histone modification has been studied on theinactive X-chromosome in ICF and Rett syndrome cells.

The results suggestedthat inactive X-chromosome in ICF cells (hypomethylated) demonstrates normalhistone modification configurations (Gartler et al., 2004). InactiveX-chromosome in Rett cells with a mutation in MeCP2 methyl-CpG binding proteinalso demonstrates normal histone modification configurations (Gartleret al., 2004). These results suggested that patterns of histonemodification are not identified by DNA methylation and methyl-CpG bindingprotein on the inactive X-chromosome.          ICF syndrome  The immunodeficiency, centromeric instability, andfacial anomalies (ICF) syndrome is an orphanautosomal recessive disease, first described in 1978 (Sterlinet al., 2016). The features of ICF syndrome includes facial dysmorphisms,hypertelorism (large distance between eyes), macroglossia (large tongue), epicanthalfolds, low set ears, low serum immunoglobin, highly exposed to infectiondiseases, flat nasal bridge, and it is distanced by multi-diverging ofjuxtacentromeric sections of chromosome 1,9, and 16 after phytohemagglutinin(PHA) stimulation of lymphocytes (OMIM #242860).

Also they may suffer fromphysical and mental impairment. It also characterized by the deficiency ofmemory (CD19+ CD27+) B cells that situated in blood and changeable cellularreduction (Sterlin et al., 2016).

The change inthe position of chromosome structure is related to DNA hypomethylation in theheterochromatin areas of Chr 1, 9 and 16 are a distinctive feature of thisdisease (Sterlin et al., 2016). ICF syndrome isassociated 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 bygermline gene mutations in DNMT3B gene (one of the DNA methyltransferase genes)(Matarazzo et al.

, 2009). They were about 50-60% cases with mutations in DNMT3Bconsidered as ICF patients, not all patients with ICF had this mutation. DNMT3Bgene is plays a significant role in mammalian development and its dysfunctionis linked to several human diseases. DNMT3B gene is encodes for a protein thatbinds 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, whichholds 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). About1/3 ICF patients shows homozygous mutation, whereas the rest shows compoundheterozygous (Matarazzo et al.

, 2009).   Also numbers of ICF syndrome patients (almost 30%) have beenidentified with a mutation in zinc-finger and BTB domain-containing 24 (ZBTB24)(Walton, Francastel and Velasco, 2014). This signifying that ICF type 2 iscaused by malfunctions of ZBTB24. ZBTB24 is a member of transcription factorthat plays a role in regulating lymphoid development and function (Walton,Francastel and Velasco, 2014). It also involves in B cell distinction (Sterlinet al., 2016). No sufficient information present about ZBTB24 at the main time,but it has been limited to heterochromatin and it can be associated withcontrolling extremely methylated areas (Sterlin et al., 2016).

The mostdistinguished signs in ICF2 individuals are mental disabilities, whereas thelack 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 ispresent ZBTB24 or DNMT3B and it is named ICFX.

However, more recent studiesindicates that ICF type 3 and ICF type 4 patients have mutations in CDCA7 andHELLS, highlighted the heterogeneity of the ICF syndrome (Sterlin et al.,2016).   Rett syndrome  Rett syndrome is a rare but severe x-linkedneurological disorder that primarily affecting girls.

It occurs once every10000-22000 live female births (Kriaucionis and Bird, 2003). Thesigns of this disorder cannot be recognized during early development untilaround 6-18 months followed by a skill regression that includes loss ofcommunication and motor skills, autism, seizures, stereotypic hand movements, microcephaly,ataxia, irregular breathing patterns, spinal curvature, gastrointestinalproblems, and mental retardation (OMIM #312750). Rett syndrome is typically relatedto serious intellectual and physical disability. The severity of the symptomsdiffers among affected children. However, even with these symptoms, patients usuallysurvive into adulthood.

Recent studies reported that the condition does notengage progressive neurodegeneration as no further regression has been occurred(Kriaucionis and Bird, 2003). Over time, girlswith Rett syndrome appear to improve in their communication skills. Rettsyndrome is caused by a single gene defects that causes of underproduction of importantbrain proteins.  The causes of Rett syndrome  Rett syndrome is a genetic disease caused by amutation in methyl-CpG-binding protein 2 (MeCP2). Studies shows that, about 80%of Rett syndrome cases are associated with a defect in MECP2 gene (Kriaucionisand Bird, 2003) that is located on X-chromosome at position Xq28 (Figure, 2).MECP2 gene is responsible for other genes function and also suppliesinstructions for making MeCP2 protein that is essential for healthy brainfunction. The accurate function of MeCP2 protein is still uncertain. Howeverthe normal function of this protein is to regulate gene expression by modifyingchromatin.

The defects on MECP2 gene is linked to several diseases. MeCP2protein is required for brain development. This protein is a chromatin-associatedprotein that can activate and repress transcription.

The MECP2 mechanism thatcauses Rett syndrome is not completely understood. However, the majority ofmissense mutations in MECP2 are closely accumulated at methyl-CpG bindingdomain (MBD) (Kriaucionis and Bird, 2003). The significance of MECP2mutations in X-linked is uncertain due to insufficient mutation frequency andrather the large capability of symptoms of Rett syndrome (Kriaucionis and Bird,2003). The mutations in MECP2 gene change the formation of MeCP2 protein andproduced insufficient amount of the protein. The dysfunction of MeCP2 proteindisables the regulation of gene expression that requires by brain cells and itmight interrupt alternative splicing of proteins that are essential for theinteraction among neurons.

 Rett syndrome is a rarely affects boy; boys who are affectedwould not live for long (beyond 2 years) as they experience serious health problemsand their phenotype are more severe than Rett syndrome. And females are mostaffected because MECP2 is X-linked and patients are heterozygous for themutated allele (Kriaucionis and Bird, 2003). Girls who are affected with MECP2 mutations, their half-cells expresswild 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 onthe long arm at position 28 as indicated by yellow arrow in the diagram.     Summary DNA methylationis important for gene expression, any mutation is related to serious humandiseases.

ICF syndrome is resulted from several type of mutation; nofunctioning link has been determined between these mutations. Four types of ICFsyndromes categorized because of different mutation caused, which includes DNMT3B,ZBTB24, CDCA7, HELLS, hence it emphasized by its genetic heterogeneity. Rettsyndrome is caused by a mutation in MeCP2 protein, mostly affected girls andrarely affects boys. However affected boys will die immediately after birth asthey had one copy of X-chromosome and they do not possess effective protectionsystem against infections. No cure is available for ICF syndrome and Rettsyndrome.