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

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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