Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene

Mandibular hypoplasia, deafness, and progeroid features, with concomitant lipodystrophy, define a multisystem disorder named MDPL syndrome. MDPL has been associated with heterozygous mutations in POLD1 gene resulting in loss of DNA polymerase δ activity. In this study, we report clinical, genetic, and cellular studies of a 13-year-old Pakistani girl, presenting growth retardation, sensorineural deafness, altered distribution of subcutaneous adipose tissue, and insulin resistance. We performed Sanger sequencing of POLD1 gene in the proband and the healthy parents. Fibroblasts obtained from dermal biopsy were evaluated for the specific hallmarks of cellular senescence and for their response to the DNA-induced damage. Patient carried the recurrent heterozygous de novo in frame deletion (c.1812_1814delCTC, p.Ser605del ) within POLD1 gene, previously detected in 16 MDPL patients. In patient's fibroblasts we observed severe nuclear envelope anomalies, presence of micronuclei, accumulation of prelamin A, altered cell growth, and cellular senescence. In addition, we observed a persistence of DNA damage after cisplatin exposure, compared to control cells. In conclusion, the MDPL nuclear and cellular findings resemble features observed in other progeroid syndromes and familial lipodystrophies. Although further investigations will be necessary, these information could be used to establish targeted therapeutic approaches.