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1. Introduction
Microcephaly is a rare neurodevelopment
disorder defined as biparietal diameter (BPD)
and for gestational phase exhausting
Brazilian-established allusion sorts small
head size characteristic that is below 3-4
standard unconventionalities and reduced
cerebral cortex region of brain (Araujo Junior
et al., 2014). Microcephaly patients may or
may not have mental retardation with mild to
severe conditions and such by way of squat
physique, annexations or hereditary earshot
loss are surplus sorts (Darvish et al., 2010).
In two common forms it can be classified;
primary microcephaly (by birth) plus
secondary microcephaly (onset after birth)
with and without other syndromic features
(COWIE, 1960). A prenatal developmental
neurogenic disorder is Primary Microcephaly
whereas secondary microcephaly is
concomitant through reformist
neurodegenerative bugs.
Autosomal recessive primary microcephaly
(MCPH) is a neurogenic mitotic syndrome
through conventional, neuronal apoptosis
neuronal voyage and neural role of
exaggerated patients. There are various
genetic and environmental causes including
Chromosomal aberrations, dented DNA as a
consequence of anxious mitotic spindle
alignment, impulsive chromosomal
abridgment, reformed indicating retort and
Maternal overconsumption of alcohol,
congenital infections and drugs taken during
pregnancy, intellect harm, metabolic
disorders such as alaninuria or revelation to
teratogenic remedies and substances taken
during pregnancy (Darvish et al., 2010)
(Faheem, Naseer, Rasool, Chaudhary,
Kumosani, Ilyas, Pushparaj, Ahmed,
Algahtani, & Al-Qahtani, 2015). Secondary
microcephaly frequently basis metabolic
ailments somewhat than primary
microcephaly and are regularly concomitant
with surplus signs and experimental signs
(Hagen et al., 2014). Inquiries of metabolic
screening, if necessary, must primarily
emphasis on maternal phenylketonuria,
phosphoglycerate dehydrogenase paucity,
and Amish fatal microcephaly (2-
ketoglutaric aciduria) as secondary bases of
microcephaly (Kelley, Robinson,
Puffenberger, Strauss, & Morton, 2002).
Sterol biosynthesis disorders,
mitochondriopathies, and hereditary
disorders of glycosylation are provoked by
the defects the sporadic metabolic bases of
primary microcephaly embrace serine
biosynthesis (von der Hagen et al., 2014).
MCPH the prevalence that arrays since
1:30,000–1: 250,000 per live-birth reliant on
the population (Zaqout, Morris-Rosendahl, &
Kaindl, 2017). In Asian and Arab populations
where, consanguineous marriages are mutual
but MCPH is scarcer in Whites than both (M.
Farooq et al, 2009). Worldwide MCPH has
been recounted in additional than 300
families and distinct patients; conversely,
frequently with merely scrubby phenotype
similes. Separately from intellectual infirmity
(IQ between 30 and 70–80), hyperactivity
and devotion deficit, dialog deferral, and a
tapered slanting forehead, MCPH patients
ordinarily do not have any auxiliary
neurological ciphers (Bhat et al., 2011;
Kaindl et al., 2010; Kraemer et al., 2016;
Passemard et al., 2009). For Autosomal
Recessive Primary Microcephaly to date 18
loci and residing genes are guilty which are
described (Figure 1) and their cytogenic
location are summarized in Figure 2
(Faheem, Naseer, Rasool, Chaudhary,
Kumosani, Ilyas, Pushparaj, Ahmed,
Algahtani, & Al-Qahtani, 2015) ; (Zaqout et
al., 2017). The utmost corporate basis of
MCPH are Biallelic mutations in ASPM
(68.6%), followed by those in the WDR62
gene (14.1%) and MCPH1 gene (8%). To
exist given the lack of mutations more
genetic loci are stagnant predictable in
known loci in circa 50 to 75% of western
Europeans or North Americans with MCPH
and almost 20 to 30% of Indians or Pakistanis
with MCPH (Verloes, Drunat, Gressens, &
Passemard, 1993); (Sajid Hussain et al.,
2013).
The up-to-date knowledge on the molecular
genetics of autosomal recessive primary
microcephaly (MCPH) counting the newly
notorious locus with its gene (MCPH1-
MCPH18) in this review article we
expansively discuss. The corresponding
genes and the proteins encoded by these
genes, their probable role in the emerging
brain (Table 1) and stated mutations of these
genes explicitly in Pakistani population
(Table 2) of the MCPH genes auxiliary, we
review. In toting, through human brain
evolutionary the latent for these genes to
achieve numerous intellectual parts methods
are conversed.
2. Molecular Genetics
i. MCPH1 (Microcephalin)
MCPH1 encodes the important regulator of
chromosome condensation (BRCT –BRCA1
C terminus) “Microcephalin protein”.
Microcephalin protein consists of 3 BCRT
domains and conserved tandem repeats of
phospho-peptide interacting amino acids
(Faheem, Naseer, Rasool, Chaudhary,
Kumosani, Ilyas, Pushparaj, Ahmed,
Algahtani, Al-Qahtani, et al., 2015; Pulvers,
Journiac, Arai, & Nardelli, 2015). This gene
is localized on chromosome 8p23 composing
14 exons, 835 amino acids, genome size and
molecular weight of 241,905 bp and 92877
Da respectively. It exists in three isoforms
obtained after splicing and an open reading
frame of about 8,032 bp (Faheem, Naseer,
Rasool, Chaudhary, Kumosani, Ilyas,
Pushparaj, Ahmed, Algahtani, & Al-Qahtani,
2015); (Venkatesh et al., 2013).
Microcephalin protein being a pleiotropic
factor imparts its significant effect in
neurogenesis; it regulates the division of
neuroprogenitor cells and prevents them from
exhaustion i.e. from microcephaly. It is the
significant regulator of telomere integrity and
tangled in DNA damage repair mechanism.
Also act as tumor suppressor in several
human cancers, in germline functions and
performs its function in brain development
and in the regulation of the normal size of
cerebral cortex (Venkatesh et al, 2013;
Pulvers et al, 2015). Some of studies have
reported that MCPH1 gene is involved in
brain size determination and as positive
selector for primate linage (Stephen H.
Montgomery & Nicholas I. Mundy, 2014; S.
H. Montgomery & N. I. Mundy, 2014). It was
considered that MCPH1 being a common
causative agent of microcephaly covering
both environmental and genetic causative
areas of microcephaly. It leads to the drastic
reduction of brain size, especially in the
region of cerebral cortex and short stature.
Magnetic resonance imaging (MRI) of the
patients revealed that the existence of
cerebral deformations, such as gyral pattern
observed in the brain and corpus collasum
hypoplasia. It is basically caused due to
premature switching asymmetric division
neuroprogenitors from symmetric division.
Mutation in MCPH1 causes the mis-
regulated chromosomal condensation,
genomic instability, delayed de-condensation
post mitosis (Liu, Zhou, & Wang, 2016). The
successful experiments for MCPH1-mouse
model generation reported mis-regulated
mitotic chromosome condensation,
deficiency in DNA repair, defective spindle
orientation and a reduced skull size with the
approximately 20% reduction in body weight
(Faheem, Naseer, Rasool, Chaudhary,
Kumosani, Ilyas, Pushparaj, Ahmed,
Algahtani, & Al-Qahtani, 2015; Zhou et al.,
2013).
ii. MCPH2 (WDR62)
The WDR62 gene, encodes the “WD repeat-
containing protein 62”, localized on
chromosome 19q13.12 composing 35
exons,1518 amino acids, genomic size of
50,230 bp with the molecular mass of 165954
Da and has four known spliced isoforms
(Faheem, Naseer, Rasool, Chaudhary,
Kumosani, Ilyas, Pushparaj, Ahmed,
Algahtani, & Al-Qahtani, 2015; Pervaiz &
Abbasi, 2016). WDR62 consists of a WD40
domain, a JNK docking domain and a MKK7
binding domain. It is a scaffold protein
involved in the pathway of the c-Jun N-
terminal kinase (Bastaki et al., 2016) and
highly expressed in neuronal precursors,
developing brain within post mitotic neurons
and in the ventricular and sub ventricular
zone in forebrain region (Pervaiz & Abbasi,
2016). This protein plays a significant part in
the formation of several cellular layers in the
cerebral cortex region during embryogenesis.
It plays a compelling character in the
proliferation and migration of neurons and in
the duplication of mother-centriole-
dependent centriole (Sgourdou et al., 2017).
Several findings revealed that WDR62
functions are somehow similar to ASPM
which is another MCPH gene. Moreover,
studies revealed that WDR62 gene, as it plays
an important part in brain cortical
development, is involved in human brain
evolutions indicted by dramatic inflation in
the size of cerebral cortex (Pervaiz et al,
2016). Mutation in WDR62 can lead to wide
range of disorders including: microcephaly,
cognitive disability, cortical malformations
and multiple transcript variants by alternative
splicing. Majority of mutations found in
WDR62 which revealed that it accounts for
around 10 % of all the cases of microcephaly.
Homozygous or heterozygous mutation in
WDR62 causes autosomal recessive primary
microcephaly with or without cortical
malformations (Naseer et al., 2017). Patients
with these mutations have HC ranging from
normal to severe. MRI of the patients with
these mutations shows numerous cortical
malformations such as pachygyria,
impulsivity, polymicrogyria, aggretion,
hypoplasia of corpus collasum, delayed
psychomotor development , simplified gyral
patterns, mental retardation with reduced
head size and lissencephaly (Faheem,
Naseer, Rasool, Chaudhary, Kumosani, Ilyas,
Pushparaj, Ahmed, Algahtani, & Al-Qahtani,
2015) (Bastaki et al., 2016; Farag et al.,
2013). Disruption of WDR62 in mouse
model altered the late neurogenesis
neocortical progenitors proliferation process
which further depicts asymmetric
centrosome inheritance abnormalities leading
towards the microcephaly in mice, and
impairs the mitotic cycle progression,
temporarily arrest at pro metaphase and
defects in spindle pole localization of
WDR62 (Farag et al., 2013; Sgourdou et al.,
2017).
