MUTATION IN PHOSPHOLIPASE C, δ1 (PLCD1) GENE
UNDERLIES HEREDITARY LEUKONYCHIA IN A PASHTUN
FAMILY AND REVIEW OF THE LITERATURE Khan AK, Khan SA, Muhammad Na, Muhammad No,
Ahmad J, Nawaz H, Nasir A, Farman S, Khan S *Corresponding Author: Saadullah Khan, Ph.D., Department of Biotechnology & Genetic Engineering, Kohat University of
Science & Technology, Banu Road, Kohat 26000, Khyber Pakhtunkhwa, Pakistan. Tel: +92-333-506-8108. Fax: +92-0922-
554-556. E-mail: saadkhanwazir@gmail.com; saad@kust.edu.pk page: 69
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DISCUSSION
The present study describes a family with characteristic
features of leukonychia. Affected individuals show
typical chalky whitening of nail both in hands and toes.
One of the affected members (III-2) also showed yellow
pigmentation at the toe nails, as observed earlier in a family
reported by Mir et al. [5].
This is the first Pashto-speaking family carrying a mutation
at position p.Cys209Arg having leukonychia with
autosomal dominant inheritance mode. In our present and
previous report [5], we have studied several patients with mutations
on the PLCD1 gene, causing a leukonychia phenotype.
However, we could not find any difference in the severity of
the nails whitening in patients carrying different mutations,
and no clear genotype-phenotype correlation emerged.
To date, only five distinct mutations have been identified
in the PLCD1 gene causing leukonychia. Of these,
three mutations underlie the autosomal recessive form of
leukonychia, while the other two mutations (including the
mutation reported in this family) are responsible for the
autosomal dominant form of the disease (Table 1). It appears
that protein truncation mutations cause the recessive
forms, while the autosomal dominant forms are caused by
missense mutations. Possibly the missense mutation could
exert a dominant negative effect on the wild-type allele
with complete loss of function.
Analysis of the protein sequence by protein prediction
tool PolyPhen2 [http://genetics.bwh.harvard.edu/ pph2/] revealed that the substitution of cysteine by arginine
(p.Cys209Arg) could potentially have a damaging
effect on PLCD1 structure. The mutation was also tested
on mutation taster, predicting disease causing.
The PLCD1 gene is composed of 15 exons. It spans a
22.17 kb region and encodes two isoforms containing 777
and 756 amino acids, respectively. It is a member of a large
superfamily of phosphoinositide-specific phospholipase
C (PLC), which is involved in the hydrolysis of phosphatidylinositol
4,5-bisphosphate (PIP2) to produce second
messengers including diacylglycerol (DG) and inisitol
triphosphate (IP3). As a result of PLCD1 gene disruption,
a significant reduction of inositol monophosphate IP1 occurs,
which is a downstream metabolite of IP3. PLC-δ1 is
highly expressed in nail matrix, hair follicles, hair matrix
and the nail bed [4,8].
It has been suggested that PLC-δ1 functions downstream
of the FOXN1 transcription factor that regulates
hard keratin gene expression essential for nail differentiation
[9]. Interestingly, loss of function mutations in the
FOXN1 gene results in defects of onycholemmal differentiation
and severe onychodystrophy in both mice and
humans [10]. Therefore, loss of PLC-δ1 function may result
in abnormal keratinization of nail plate due to aberrant
expression of hard keratins causing leukonychia phenotype.
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