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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RESULTS
Clinical Findings and Mutational Analysis. All affected
individuals of the family, studied here, showed typical
features of hereditary leukonychia. These include chalky
white, consistent with total leukonychia on their hands and
feet. Whiteness of the nails involved the entire nail, including
the lunula, and was present since birth. One affected
individual (III-2) displayed incomplete leuko-nychia with
yellowish coloration in the distal parts of the nail plate in the
middle toe nail. All 20 nails had normal growth rates (Figure
1B). Other abnormalities of skin, hair, teeth and sweating
were not observed in any affected member of the family.
Based on phenotypes, the already reported PLCD1
gene involved in the particular disorder on chromosome
3p21.3-p22, was planned for sequencing before embarking
into the whole exome sequencing. Subsequently, all
fifteen exons and splice sites of the PLCD1gene were sequenced in all available affected and unaffected members.
Affected individuals of the family with autosomal
dominant inheritance displayed heterozygous missense
mutation involving a T to C transition at nucleotide position
625 in the PLCD1 gene, resulting in the substitution
of cysteine to arginine amino acid at position 209
(p.Cys209Arg) (Figure 2A). The variant is present in the
genomeAD data-base in overall frequency of 0.00006095
in the heterozygous state.
A homology modeling techniques was used to identify
the structural role of the mutated positions, we analyzed
their intra-molecular interactions and compared
wild-type with mutant model (Figure 2B-2D). We were
able to identify intra-molecular changes only for the amino
acid substitution at residue Cys209. In fact, Cys209 was
not involved in any interaction with nearby residues, while
in the mutant model, Arg209 forms hydrogen bonds with
the nearby Ile145, which, due to the difference in bonding,
may provide a local difference in the helix structure
as seen from the figure (Figure 2C and 2D).
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