The Genetics of Pituitary Adenomas

Fedele, Monica; Pierantoni, Giovanna Maria

doi:10.5772/16639

Cited by 3 publications

(4 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is often somatically mutated in the pituitary adenomas, i.e. Cushing's disease (14,15). This gene is under evolutionary constraint with five observed loss of function variants (LoF, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Of note the Met415 residue, often found somatically mutated in Cushing's disease, i.e. adenomas of the pituitary (14,15), is only a few residues after the end of the loop bearing Gly406, in a stretch of residues [AYMLVY] conserved in USP48 orthologs and in a region positioned close to ubiquitin (< 8 Å) and within 12 Å of active site residues Cys98 and His353 (Figure 2A). The Thr739, residue mutated in the Dutch patient, is situated in a conserved T-D- [VE].L-Y stretch found in 185 Swiss-Prot sequences.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss

Bassani

Beelen

Rossel

et al. 2021

Human Molecular Genetics

View full text Add to dashboard Cite

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant affects a loop that controls binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner’s membrane, and in the transient Kolliker’s organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 Hz and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining exome sequencing, animal modeling, immunohistology and molecular assays.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss

Bassani

Beelen

Rossel

et al. 2021

Human Molecular Genetics

View full text Add to dashboard Cite

show abstract

“…[ 2 ] Pituitary tumors are present in 40% of patients with MEN1 and are usually prolactin-producing or non-functioning tumors. [ 3 ] Type II gastric neuroendocrine tumors (NETs) are associated with MEN1, often affecting both the fundus and body of the stomach. Most often, they are asymptomatic and are found in the workup of anemia or symptoms of peptic ulcers.…”

Section: Introductionmentioning

confidence: 99%

“…Primary hyperparathyroidism is usually the first manifestation detected and has high penetrance in individuals with MEN1, even at younger ages [2] . Pituitary tumors are present in 40% of patients with MEN1 and are usually prolactin-producing or non-functioning tumors [3] . Type II gastric neuroendocrine tumors (NETs) are associated with MEN1, often affecting both the fundus and body of the stomach.…”

Section: Introductionmentioning

confidence: 99%

A case report of multiple endocrine neoplasia type 1 and autoimmune disease

Chaves

Silva²,

Pereira

et al. 2021

Medicine

View full text Add to dashboard Cite

Rationale: Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. Herein, we present a case of MEN1 with multiple endocrine and autoimmune disorders. Patient concerns: A 50 years old female with a 25 years history of complicated nephrolithiasis presented with primary hyperparathyroidism. Diagnoses: Over several decades, she was diagnosed with recurrent primary hyperparathyroidism, autoimmune thyroiditis, multinodular goiter, pernicious anemia, metastatic gastric type 1 neuroendocrine tumor, macroprolactinemia, gonadotropin deficiency, mucosa-associated lymphoid tissue lymphoma of the thyroid gland, positive anti-calcium sensor receptor antibodies, and BRCA 1/2 -negative invasive breast cancer. The autoimmune regulator gene was sequenced, but no pathogenic variants were found. Next-generation sequencing revealed both a pathogenic MEN1 mutation and a benign CDC73 gene variant. Familial genetic screening revealed a large kindred with multiple carriers of one or both genetic variants ( MEN1 = 19; CDC73 = 7). Interventions: The patient underwent surgical excision of three parathyroid glands, total thyroidectomy and breast tumorectomy plus tamoxifen, and monthly injections of octreotide. The patient and family members with the MEN1 mutation are under a life-long surveillance program for MEN1 prototypic tumors. Outcomes: The patient was stable and alive during a 24-years follow-up period. Lessons: With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients.

show abstract