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

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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