CHARGE (CHD7) gene as the plausible cause for CHARGE

syndrome: This syndrome
was first discovered by Hall in 1979 in children that exhibited some common
congenital abnormalities such as Coloboma,
Heart defects, choanal Atresia, Retarded growth and development, Genital hypoplasia, Ear
abnormalities, thus given the acronym CHARGE (Pagon et
al., 1981). The prevalence of the syndrome ranges from one in every
8,500-12,000 births. The diagnosis is based on the presence of five major symptoms
such as coloboma, choanal atresia, ear abnormalities, cranial nerve dysfunction
and bone abnormality or four of the major symptoms and three of the minor
symptoms such as genital hypoplasia, retarded growth, lip cleft/palate,
tracheoesophageal fistula and delay in development (Pinto et
al., 2005). The genital hypoplasia of these patients is mainly due to
HH associated with anosmia or hyposmia due to olfactory bulb abnormalities
similar to Kallmann syndrome patients (Pinto et
al., 2005). However, this syndrome was distinguished from Kallmann
syndrome based on the other non-reproductive symptoms. This is mostly a
sporadic syndrome with few reported familial cases with a high prevalence in monozygotic
twins. Vissers et
al. (2004) reported a 2.3 Mb de novo micrdeletion detected in chromosome
8 (8q12) overlapping chromodomain
helicase DNA-binding protein 7 (CHD7)
gene as the plausible cause for CHARGE syndrome two patients. Subsequently,
several other point mutations including premature stop codons, missense and
splice site variants were detected in ~90% CHARGE syndrome patients (Vissers
et al., 2004). The CHD7 gene
consists with 38 exons and code for chromodomain helicase DNA binding protein
7. The protein is involved in chromatin remodelling and gene expression and expressed
in many foetal tissues including eye, cochlea, brain, heart, kidney, stomach
and skeleton. CHARGE syndrome patients have shown many congenital abnormalities
that originated during embryonic development in these organs (Vissers
et al., 2004). All the mutations were found in heterozygous state in
these patients suggesting haploinsufficiency of the gene is responsible for the
development of CHARGE syndrome. Since CHARGE syndrome patients show several key
features of Kallmann syndrome, its speculated that CHD7 could be involved in transcription
of the genes that are activated through FGFR1 signalling necessary for
olfactory bulb development (Pinto et
al., 2005). Certain features of CHARGE syndrome such as heart defects,
choanal atresia, abnormal middle ear and cleft lip can be corrected by surgery.
Cochlear implants are also used to treat the patients with severe hearing loss.
Growth hormone therapy has shown to help to increase the height of the patients
that show retarded growth. Same as in Kallmann syndrome patients, the GnRH
therapy and sex steroid therapy is used to treat the HH condition and delayed
puberty (


We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now

            The most common treatments available at present are sex hormone,
GnRH and gonadotropin (FSH and LH) therapy. The primary aim of gonadal hormonal
therapy is to induce puberty and development of secondary sex characteristics, mainly
virilisation in males and breast development in females (Dode and Hardelin, 2008). In
males testosterone therapy is mainly done via intramuscular injections every
two to three weeks (intramuscularly administered testosterone has approximately eight days
half-life), or other less commons methods such as testosterone pellets, patches
or bio adhesive testosterone tablets (Bhasin et al., 2010). After the
initiation of puberty, continued injections are required to stimulate the
secondary sex characteristics development and maintain normal biological levels
of hormone in the blood.  Testosterone further
converted into dihydrotestosterone (DHT) by 5? reductase in male leydig cells
and DHT is the key androgen responsible for secondary sex
characteristics development and masculinization of external genitalia in males.
In females, depending on the age of the patients, transdermal estrogen patches
with low doses are given at the beginning to induce onset of puberty growth and
gradually increase the dose to induce breast development, uterine growth and
later administration of progesterone helps continuation of menstrual cycles (Ankarberg-Lindgren et al., 2014) . When these
patients desire to be fertile pulsatile GnRH and/or gonadotropin hormonal
therapy is used. GnRH therapy is usually performed for about 220 days using a
portable, computerized infusion pump connected to a subcutaneous catheter. Supplementation
of GnRH starts with a low dose (i.e. 1 ?g) released set intervals (i.e. every
90 mins) and then increases the does to (i.e. 5 ?g) (Skarin et al., 1982). Supplemented GnRH
acts on 7 transmembrane G-coupled receptors in the anterior pituitary
gonadotropes and mainly works though Gs and Gq proteins. Gs activates adenylyl
cyclase enzyme to convert ATP into cyclic AMP and this second messenger
subsequently activates protein kinase A (PKA). Protein kinase A phosphorylates
and activates transcriptions factors necessary to activate the transcription of
FSH and LH genes. Gq protein activates phospholipase C enzyme to convert PIP3
to IP3 and DAG and activates PKC. This will increase intracellular Ca2+ flux to
stimulate the exocytosis of secretory vesicles to release mature FSH and LH (Naor, 2009). In males, LH acts on 7 transmembrane
G-coupled receptors on leydig cells and works through Gs protein. Protein kinase
A phosphorylates and activates transcriptions factors that are necessary to
activate the transcription of genes involved in testosterone production. FSH acts on 7 transmembrane
G-coupled receptors on
Sertoli cells and works mainly through Gs and Gq proteins. These kinases
activate the aromatase enzyme to convert testosterone into
estrogen in the Sertoli cells. These sex steroids stimulate libido, gonadal
development and spermatogenesis (Skarin et al., 1982). In females LH acts
on receptors on theca cells that work through both Gs and Gq. Activated PKA
through this signaling will activate the transcription of genes necessary for
androgen production. This androgen then will go to granulosa cells where FSH
acts on. FSH works through oth Gs and Gq and activate the aromatase enzyme to
convert androgen into estrogen. Increase in estrogen has a positive feedback on
anterior pituitary to release FSH and LH during follicular phase and this stimulate
folliculogenesis and ovulation. These sex steroids have cytosolic receptors in the
target reproductive and brain tissues that upon ligand binding undergo
conformational change and dissociate heat shock proteins and translocate into
the nucleus.