Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1 –PPP1CB complexes

AbstractRASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identifiedLZTR1, PPP1CB andMRAS as new causative genes in RASopathies. However, information on the phenotypes ofLZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants ofLZTR1, PPP1CB, andMRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eightLZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novoPPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygousLZTR1 variants, suggesting autosomal recessive inheritance. All probands withLZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1 –PPP1CB complex. Cells transfected with a small interfering RNA againstLZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1 –PPP1CB complex as a component of the...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research