ABSTRACT
Lynch syndrome is caused by inactivating variants in DNA mismatch repair genes, namely MLH1, MSH2, MSH6 and PMS2. We have investigated five MLH1 and one MSH2 variants that we have identified in Turkish and Tunisian colorectal cancer patients. These variants comprised two small deletions causing frameshifts resulting in premature stops which could be classified pathogenic (MLH1 p.(His727Profs*57) and MSH2 p.(Thr788Asnfs*11)), but also two missense variants (MLH1 p.(Asn338Ser) and p.(Gly181Ser)) and two small, in-frame deletion variants (p.(Val647-Leu650del) and p.(Lys678_Cys680del)). For such small coding genetic variants, it is unclear if they are inactivating or not. We here provide clinical description of the variant carriers and their families, and we performed biochemical laboratory testing on the variant proteins to test if their stability or their MMR activity are compromised. Subsequently, we compared the results to in-silico predictions on structure and conservation. We demonstrate that neither missense alteration affected function, while both deletion variants caused a dramatic instability of the MLH1 protein, resulting in MMR deficiency. These results were consistent with the structural analyses that were performed. The study shows that knowledge of protein function may provide molecular explanations of results obtained with functional biochemical testing and can thereby, in conjunction with clinical information, elevate the evidential value and facilitate clinical management in affected families.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , DNA Mismatch Repair , MutL Protein Homolog 1 , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Humans , Male , MutL Protein Homolog 1/genetics , Female , DNA Mismatch Repair/genetics , Middle Aged , MutS Homolog 2 Protein/genetics , Adult , Tunisia , Pedigree , Turkey , Aged , Mutation, MissenseABSTRACT
Skin lesions in chronic lymphocytic leukemia (CLL) have been reported in between 4% and 20% of patients with CLL and are a rare entity compared with T-cell leukemia. They can present mainly as leukemic cutis or, frequently, as secondary lesions such like urticaria, itching, pyoderma gangrenosum, cutaneous vasculitis, Sweet's syndrome, and erythroderma. We report on an adult patient who developed a skin lesion of forearms and hands, leading to the discovery of isolated cutaneous CLL after two biopsies. Isolated CLL cutaneous location is very rare and may be diagnosed late, as in the case of our patient. A better knowledge of the course of the illness and rapid diagnosis of this CLL cutis leukemia will enhance the therapeutic efficacy of the disease.
