The Y606C RET mutation causes a receptor gain of function.

Context: Medullary thyroid carcinoma (MTC) is the most common feature of multiple endocrine neoplasia type 2A (MEN2A) and occurs in almost all patients affected by germline RET mutations.

Objective: We identified and characterized an activating germline RET point mutation (G>A substitution leading to the heterozygous missense mutation Y606C in exon 10), in a 58-year-old female affected by MTC.

Design: The RET/Y606C and RET/C620Y, obtained by site-directed mutagenesis, as well as the RET/wild-type (wt) were cloned in an expression vector and transiently transfected in NIH3T3 fibroblasts.

Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations.

Context: The von Hippel-Lindau (VHL) syndrome is an inherited multitumour disorder characterized by clinical heterogeneity and high penetrance. Pheochromocytoma (Pheo) is present in 10%-15% of cases and can be isolated or associated with other lesions such as haemangioblastomas, kidney cysts or cancer and pancreatic lesions. In VHL patients, Pheos generally secrete norepinephrine and are located in the adrenals.

Genetics and biology of pheochromocytoma.

The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively.

SDH mutations in patients affected by paraganglioma syndromes: a personal experience.

Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest-derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL.

Estrogen receptor alpha promoter polymorphism: stronger estrogen action is coupled with lower sperm count.

Background: Although the importance of estrogens in male reproduction is indisputable, little attention has been paid to the role of estrogen receptor (ER) gene mutations in male infertility. Significant correlation between (TA)n repeat allelic variants and lumbar bone mineral density was previously observed in the promoter region of the ERalpha gene, indicating that allelic combinations with higher number of (TA)n repeats are functionally more active genetic variants.

Methods: We studied the (TA)n repeat polymorphism situated in the promoter region of the ERalpha gene in a large group of infertile and normospermic men (n = 347).