A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Honda, Munehiro; Tsukada, Toshihiko; Tanaka, Hiroyuki; Maruyama, Kouji; Yamaguchi, Ken; Obara, Takao; Yamaji, Taketo; Ishibashi, Masayoshi

doi:10.1530/eje.0.1420138

Cited by 27 publications

(20 citation statements)

References 28 publications

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“…The majority of FIHP with MEN 1 mutations presented with mild hypercalcemia and multiglandular disease or parathyroid hyperplasia, similar to what is usually seen in MEN1 (8)(9)(10)(11)(12)(13). On the other hand, in FIHP families where HRPT2 gene mutations have been detected, the clinical presentation is more severe and in all cases the histopathological diagnosis was parathyroid carcinoma or adenoma, frequently associated with atypical or cystic features similar to those seen in HPT-JT syndrome (13)(14)(15).…”

Section: Introductionmentioning

confidence: 60%

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Silveira

Dias²,

Marinho³

et al. 2008

Arq Bras Endocrinol Metab

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It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafi bromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafi bromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75%), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotypegenotype correlation in larger series, to best defi ne their treatment. RESUMO Formas Familiares de Hiperparatireoidismo Relacionadas a Mutações no Gene HRPT2: Estudos Moleculares Poderiam Direcionar Procedimentos Cirúrgicos?A melhor conduta nas formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2 ainda é controvertida. Cirurgias conservadoras, minimamente invasivas ou mais agressivas já foram propostas por diferentes grupos. Objetivamos estudar a seqüência e a expressão do gene HRPT2, além do desfecho clínico, após seguimento de até 32 anos de uma família brasileira com hiperparatireodismo familiar isolado (FIHP). Utilizamos dados clínicos e bioquímicos, seqüenciamento direto do HRPT2 além de análise da expressão da parafi bromina através da RT-PCR e imunohistoquímica. Foi identifi cada mutação nonsense no éxon 1 (c.96G>A)(p.Trp32X) em todos os membros afetados que foram estudados. A análise do mRNA transcrito, através da RT-PCR, demonstrou ausência do transcrito no tecido tumoral. A imunohistoquímica também evidenciou ausência da parafi bromina. Nessa família houve alta (75%) prevalência de recorrência ou persistência da doença após paratireoidectomia parcial o que nos levou a considerar fundamental discutir uma abordagem cirúrgica mais agressiva com os outros familiares portadores da mutação caso critérios de indicação cirúrgica sejam atingidos. Dessa maneira, até que estudos mais amplos estabeleçam uma correlação genótipo-fenótipo no hiperparatireoidismo familiar relacionado a mutações no HRPT2, a abordagem cirúrgica deverá ser individualizada. Silveira et al. HRPT2 mutations in FIHP and surgery

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Section: Introductionmentioning

confidence: 60%

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Silveira

Dias²,

Marinho³

et al. 2008

Arq Bras Endocrinol Metab

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“…The mouse menin cDNA was obtained by PCR amplification using a spleen cDNA library as the template as previously described. (15) The previously reported variant sequences and their corresponding phenotypes were according to the references as follows: P12L, L22R, K119del, H139D, A160P, A242V, A309P, T344R, E363del, W436R and R460X; (16) G28A; (17) D153V and A411P; (18) G156C, F364C and F447L; (19) A160T and D418N; (20) R171W and E366D; (21) V184E; (9) T197I and Y353del; (22) W220L and Y351N; (23) R229L; (24) S253W and E274A; (11) E255K; (10) Q260P; (25) L264P and L267P; (26) P277H; (27) G305D; (12) H317Y; (14) P320R; (28) P320L; (29) L414del; (30) and S555N. (31) The expression vector pCMV-BICEP-4 (Sigma, St. Louis, MO, USA), designed to allow translation of two proteins from one bicistronic mRNA, was used for transient co-expression of N-terminal FLAG-tagged and Myc-tagged menin proteins.…”

Section: Methodsmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

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Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance. (Cancer Sci 2011; 102: 2097-2102 M enin is a tumor suppressor protein encoded by MEN1, a gene responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome typically characterized by the development of multiple tumors in the pituitary, parathyroid and enteropancreatic endocrine tissues.(1,2) Menin is a nuclear protein having C-terminal nuclear localizing signal sequences, (3) and exhibits modulatory activity on gene expression such as repression of JunD-dependent transcription. (4) Diverse roles have been implicated for menin, including cell cycle control, cell differentiation and DNA repair, which are likely to be conferred by interaction with various menin-binding proteins.(2) Menin is considered to be a scaffold protein tethering such proteins to specific gene loci.(5) Although the mechanism of how menin is involved in gene regulation has been elucidated to some extent, the basis for tissue-specific tumorigenesis in MEN1 remains unknown.Heterozygous germline mutations of the MEN1 gene are found in 70-90% of patients clinically diagnosed as MEN1. (6) More than 500 different loss-of-function mutations have been identified, which are distributed throughout the gene with no apparent hot spot.(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathy...

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“…(4) Some mutation carriers in these FIHP pedigrees are devoid of any signs of primary hyperparathyroidism, even at a relatively advanced age. (24) These findings suggest that some mutations found in FIHP and apparently sporadic parathyroid tumor may specifically cause these MEN1-related, milder disorders (Table 1). …”

Section: Structure and Expression Of The Men1 Genementioning

confidence: 91%

MEN1 gene and its mutations: Basic and clinical implications

Tsukada¹,

Nagamura²,

Ohkura³

2009

Cancer Science

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Heterozygous germline mutations of the tumor-suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by pituitary, parathyroid, and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and related disorders. Neither mutation hot spot nor phenotype-genotype correlation has been established in MEN1 although some missense mutations may be specifically associated with a phenotype of familial isolated hyperparathyroidism. The gene product menin has been implicated in multiple roles, including gene transcription, maintenance of genomic integrity, and control of cell division and differentiation. These multiple functions are likely to be conferred by association with multiple protein factors. Occurrence of MEN1-causing missense mutations throughout menin also suggests the requirement of multiple binding factors for its full tumor-suppressive activity. The effect of menin depletion is highly tissue specific, but its underlying mechanism remains to be elucidated. A DNA test for MEN1 germline mutations is a useful tool for diagnosis of MEN1 although it needs further improvements. The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors. So far, MEN1 gene mutations have not been implicated in any other human diseases.The product of the MEN1 gene, menin, is a 610-amino acid protein that exhibits no apparent sequence similarity to any other known protein.(1) Thus, its biochemical function can not be deduced from its structure. In the last decade, a number of studies have demonstrated physical and functional associations between menin and diverse proteins of known function, shedding light on its molecular function. These menin-interacting proteins include nuclear proteins such as transcription factors, histone deacetylases, and histone methyltransferases, suggesting that menin is involved in gene transcription. Several lines of evidence also suggest that menin is involved in the maintenance of genomic integrity. Although menin is localized mainly to cell nuclei, possible extranuclear functions have not been excluded because various cytoplasmic proteins bind to menin.Although the molecular function of menin is still poorly understood, identification of the MEN1 gene has enabled a direct DNA test for predisposition to MEN1. In the present review, recent findings on the MEN1 gene are summarized and its mutations are discussed from basic and clinical points of view. Structure and expression of the MEN1 geneThe human MEN1 gene comprises 10 exons distributed over 7 kb in the chromosome region 11q13 and encodes mRNA of approximately 2.8 kb (Fig. 2).(1) Exons 2 through 10 encode th...

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A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Cited by 27 publications

References 28 publications

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

MEN1 gene and its mutations: Basic and clinical implications

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