A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation

Abstract

Trichilemmal cysts are common hair follicleederived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole-exome sequencing of DNA from the blood samples of 5 affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, this study identified a combination of the Phospholipase C Delta 1 germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. The analysis of tissue from several cysts revealed that an additional somatic Phospholipase C Delta 1 mutation on the same allele is required for cyst formation. In two different functional in vitro assays, this study showed that the protein function of the cyst-specific 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta-1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.

PLCD1 and Pilar Cysts

“…A monoallelic "two-hit" mechanism leads to trichilemmal cyst formation To date, dominant truncating and recessive missense germline variants in PLCD1 have been identified in patients with familial leukonychia (Kiuru et al, 2011). In this study by Hörer et al (2019), a dominantly inherited haplotype with a synonymous and missense variant seen in tandem constitutes a "high-risk allele", and this genetic difference may account for the lack of leukonychia in these patients. This allele predisposes to the acquisition of in cis somatic variants within the C2 domain of PLCd1, which is associated with cyst formation.…”

“…This work by Hörer et al (2019) is important as it highlights PLCd1 as an important protein in the maintenance of human hair follicle homeostasis. In addition, the PLCD1 "high-risk" allele identified may inform the interpretation of genetic tests in families with trichilemmal cysts.…”

Hereditary Trichilemmal Cysts are Caused by Two Hits to the Same Copy of the Phospholipase C Delta 1 Gene (PLCD1)

“…Since we have not performed functional studies, we can only speculate on the mechanism that the genetic changes result in the trichilemmal cyst phenotype. However, Horer and coworkers 19 have shown that the somatic and germline mutations cause additive loss in PLCD1 enzyme activity. Thus, somatic and germline mutations in the same allele may combine to cause loss of function thereby reducing the amount of active enzyme.…”

TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours

“…Regarding the molecular mechanisms responsible for developing these cystic lesions, genetic susceptibility was described for simple TC in some cases: hereditary cases may develop with an autosomal dominant type of transmission, involving incomplete penetrance [1,20,21]. TC development has been recently related with phospholipase C delta 1 (PLCD1), probably via an inherited PLCD1 high-risk allele and somatic spontaneous mutation on the other allele [20,21]. Very little mutation analysis has been performed on PTTs: there were described genetic anomalies, mainly aneuploidy, within some PTT [17].…”

“…Some reports had related these genetic alterations with malignant change [22,23], associated occasionally with TP53 deletion [12]. The precise mechanism responsible of the proliferative ability of PTT has been not yet clarified, but the accumulation of mutations on tumour suppressor genes seems a possible option [20].…”