A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A

The Journal of Clinical Endocrinology and Metabolism
S LatteyerL C Moeller

Abstract

Multiple endocrine neoplasia type 2 (MEN2) is usually caused by missense mutations in the proto-oncogene, RET. This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later. Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay. Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET. The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of...Continue Reading

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Citations

Nov 20, 2016·Nature Reviews. Endocrinology·UNKNOWN NGS in PPGL (NGSnPPGL) Study GroupPatricia L M Dahia
Jan 23, 2018·Current Hypertension Reports·Joseph M PappachanFahmy W F Hanna
Aug 1, 2019·Thyroid : Official Journal of the American Thyroid Association·Xiao-Ping QiJian-Qiang Zhao
Jul 11, 2019·BMC Medical Genomics·Larissa V BimJanete M Cerutti
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Jun 18, 2020·Thyroid : Official Journal of the American Thyroid Association·Annie MathewVera Tiedje
Dec 20, 2020·Clinical Endocrinology·Jonathan Mark FusseyMartina Owens

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