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Hyperparathyroidism-Jaw Tumor Syndrome in Roma Families from Portugal Is Due to a Founder Mutation of the HRPT2 Gene

Centro de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Francisco Gentil, Centro Regional de Oncologia de Lisboa, Sociedade Anónima (B.M.C., M.-A.S., L.G.S., V.L.), 1099-023 Lisboa, Portugal; Molecular Endocrinology Group, Nuffield Department of Clinical Medicine, Botnar Research Center, Nuffield Orthopedic Center, University of Oxford (B.M.C., K.J.B., B.H., R.V.T.), Oxford, United Kingdom OX3 7LD; Serviço de Endocrinologia, Hospital Curry Cabral (L.G.), 1069-166 Lisboa, Portugal; Serviço de Endocrinologia, Hospital de S. João (D.C.), 4200 Porto, Portugal; and Centro de Saúde de Elvas (A.O.), 7350 Elvas, Portugal

Address all correspondence to: Dr. Valeriano Leite, Centro de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Francisco Gentil, Centro Regional de Oncologia de Lisboa, Sociedade Anómina, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal. E-mail: vleite{at}ipolisboa.min-saude.pt.

	Abstract

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The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors and ossifying jaw fibromas. The gene causing HPT-JT, HRPT2, is located on chromosome 1q31.2 and consists of 17 exons that encode a 531-amino acid protein, designated parafibromin. We recently identified six Roma families in Portugal with 56 members (11 affected and 45 asymptomatic), who had the HPT-JT syndrome. We postulated that they may have a common ancestor and that the HPT-JT syndrome may be due to a mutation of the HRPT2 gene. Haplotype analysis using 14 chromosome 1q24-q32 polymorphic markers showed that the 11 affected individuals shared a common haplotype defined by seven markers that spanned an approximately 12.5-cM region, flanked centromerically by D1S202 and telomerically by D1S306. DNA sequence analysis identified a 2-bp (TG or GT) frameshift deletion in exon 8, which predicts a truncated parafibromin protein, in all 11 affected individuals. This mutation was also found in 19 unaffected individuals (age range, 12–74 yr) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. Thus, the HPT-JT syndrome in six Roma families from Portugal is due to a novel founder mutation in the HRPT2 gene.

	Introduction

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PRIMARY HYPERPARATHYROIDISM (HPT), which may result from parathyroid adenomas, hyperplasia, or carcinoma, has an incidence of 1:1000 (1) and is most frequently encountered as a nonfamilial disorder (2). However, HPT has been associated with a number of hereditary syndromes, including multiple endocrine neoplasia (MEN) type 1 (MEN1) and type 2A (MEN2A) (3, 4, 5, 6, 7), and familial isolated HPT (8). A distinct syndrome, named HPT-jaw tumor (HPT-JT) with an autosomal dominant mode of inheritance, predisposing to the development of parathyroid and jaw tumors, has also been described (9, 10, 11, 12). The risk of parathyroid carcinomas is greatly increased in HPT-JT families (12, 13, 14, 15, 16). The bone lesions characteristic of HPT-JT are ossifying fibromas of the maxilla and/or mandible, although they may occur elsewhere in the skeleton (9, 10). In addition, renal lesions have been described, including Wilms’ tumors, hamartomas, and polycystic disease (10, 11, 12, 13, 14, 15, 16, 17). The gene causing HPT-JT (10, 11, 12, 14, 15, 16), had been localized to chromosome 1q24-q32, and the occurrence of loss of heterozygosity in some tumors indicated that the gene was likely to be a tumor suppressor (11, 12, 13, 16). Characterization of genes from a critical 12-cM region led to the identification of the causative gene (18), named HRPT2, which consists of 17 exons that encode a novel 531-amino acid protein, referred to as parafibromin (18). The HRPT2 gene is ubiquitously expressed as an approximately 2.7-kb transcript, with an additional approximately 4.5-kb transcript also present in all tissues studied (18). No homologies to known protein domains have been found, but moderate identity (32%) and similarity (54%) to a Saccharomyces cerevisiae protein known as Cdc73p, which is an accessory factor associated with an alternative RNA polymerase II, important in transcriptional initiation and elongation in yeast, was observed. However, the functional role of parafibromin remains to be elucidated. To date, 16 inactivating germline HRPT2 gene mutations have been reported in HPT-JT families (18, 19). We recently identified in Portugal six families of Roma origin, who had features of the HPT-JT syndrome and postulated that they may have a common ancestor and an HRPT2 gene mutation. We investigated this by haplotype analysis and by DNA sequence analysis of the HRPT2 gene.

	Subjects and Methods

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Patients and families

Patients gave their written informed consent to participate in this study, which was approved by the ethics committee of the Instituto Português de Oncologia. Fifty-six individuals from six families (Fig. 1) from the Roma ethnic group originating from Portugal were clinically, biochemically, and radiologically assessed for manifestations of HPT-JT. Biochemical investigations included estimations of serum calcium, phosphate, alkaline phosphatase [by colorimetric determination using a Synchron clinical systems CX7D (Beckman Coulter, Fullerton, CA)], and PTH [measured by immunoradiometric assay with the kit ELSA-PTH (CIS, Gif-Sur-Yvette, France)]. Hematoxylin- and eosin-stained sections from each tumor were evaluated histologically by two pathologists to classify the tumors according to the WHO and Armed Forces Institute of Pathology histological typing of tumors of the parathyroid glands (20, 21). Eleven individuals (four males and seven females) showed features of the HPT-JT syndrome (Table 1). Thus, nine members were found to have HPT, and six underwent parathyroidectomy. Seven parathyroid adenomas (two atypical and two cystic) were surgically removed from six affected members. The atypical parathyroid adenoma excised from patient II.9 (family 3) measured 3 x 2.5 cm and was encapsulated. Serial sections showed multifocal invasion of the tumor capsule. The cells were organized in sheets, follicles, and trabecular patterns. No vascular invasion, extension of the neoplastic tissue into the adjacent tissues, or metastases were documented. The atypical parathyroid adenoma excised from patient II.9 (family 6), measured 3 x 2.5 cm and was encapsulated. Foci of microscopic necrosis and cellular atipia were documented. This tumor displayed vascular invasion, trabecular arrangement of tumor cells, and abundant mitoses. No invasion of contiguous structures or metastases were observed. The two tumors classified as cystic adenomas, from patients II.2 (family 2) and II.1 (family 4), measured 4.0 and 2.5 cm in diameter, respectively, and showed a single cystic area occupying most of the tumor, surrounded by a thick wall, which contained areas with parathyroid cells. The two parathyroid adenomas removed from patient II.2 (family 1) measured 3.0 and 1.8 cm, were encapsulated, and were predominantly composed of oxyphilic cells. The parathyroid tumor from patient III.3 (family 1), measuring 2.0 cm in diameter, was described as an adenoma consisting almost entirely of chief cells. All 11 patients underwent clinical assessment for jaw tumors, eight of whom also had radiological assessment, and two of these were found to have jaw tumors, which were surgically removed and histologically identified to be ossifying fibromas of the jaw. Of the renal lesions commonly associated with HPT-JT (Wilms’ tumors, hamartomas, and cysts), only cysts were found in two (patients 3 and 8) of the nine patients who underwent renal ultrasonography.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Haplotype analysis of individuals from six Portuguese Roma families. Haplotypes were defined by using 14 polymorphic markers from chromosome 1q24-q32. This revealed that 30 of the 56 family members studied (11 affected and 19 unaffected) shared a common haplotype defined by the polymorphic loci D1S222, D1S428, D1S422, D1S412, D1S413, D1S2853, and D1S2622, that spanned an approximately 12.5-cM interval, encompassed between D1S202 [recombinant (R)] and D1S306 (R). The location of the HRPT2 gene, which is between D1S422 and D1S412, is indicated. The affected haplotype is defined by the alleles (6 3 9 7 1 10 11 ). The affected and unaffected haplotypes are indicated as A and U, respectively, and the absence and presence of mutations (see Fig. 2) in the HRPT2 gene are indicated by + and –, respectively, under each haplotype. These results indicate that these six Roma families are highly likely to be related through a recent common ancestor. Individuals are represented as male (squares); female (circles); affected with HPT (symbols with blackened upper left quadrant), in some cases associated with cystic (Cy) or atypical (Aty) adenomas; affected with ossifying fibromas of the jaw (symbols with blackened lower left quadrant); affected with renal cysts (symbols with blackened upper right quadrant); and asymptomatic mutant gene carriers (symbols containing a black dot). Probands in each family are indicated by arrows. The age (in years) either at the time of diagnosis (asterisk), for the 11 affected members (Table 1), or at the last biochemical screening, for the 19 unaffected carriers, is indicated below for each individual. All 19 asymptomatic carriers were normocalcemic, with normal serum PTH concentrations, and had jaw tumors excluded on clinical assessment. Nine of these individuals also had jaw and/or renal lesions excluded by jaw x-ray (jXR) and/or renal ultrasound (rUS).

Venous blood samples were obtained from 56 members (11 affected and 45 asymptomatic individuals) of the six families (Fig. 1). Venous blood samples were also obtained from 26 normal, unrelated individuals from the Roma ethnic group. Leukocyte DNA was extracted as described previously (22, 23). Fourteen microsatellite polymorphisms from chromosome 1q24-q32 (locus order: cen-D1S240-[D1S2848, D1S444-D1S254]-D1S202-D1S222-D1S428-D1S422-D1S412-D1S413-D1S2853-D1S2622-D1S306-D1S456-tel) were detected by PCR using ³²P-radiolabeled oligonucleotide primers and leukocyte DNA, as previously described (12, 22, 24, 25).

DNA sequence analysis of the HRPT2 gene

Seventeen pairs of primers (details available upon request) were used for PCR amplification of the 17 coding exons and adjoining splice junctions of the HRPT2 gene, as previously described (18). The DNA sequences of gel-purified PCR products were determined using the Thermo Sequenase II Dye Terminator Cycle Sequencing Premix Kit (Amersham Pharmacia Biotech, Little Chalfont, UK) and a semiautomated detection system (ABI 373 sequencer, PE Applied Biosystems, Foster City, CA) (26). DNA sequence abnormalities were confirmed by allele-specific oligonucleotide (ASO) hybridization analysis, using conditions previously described (27). For the ASO analysis, the wild-type oligonucleotide sequence was 5'-TCTTCAATCTGTAAAAGCCA-3', and the mutant oligonucleotide was 5'-TTCTTCAATCTAAAAGCCAG-3'. The temperature used for hybridization and that used for washing the membranes were 50 and 64 C, respectively, for both wild-type and mutant oligonucleotides.

Statistical analysis

Statistical analysis was performed using a ² test as previously reported (28, 29).

	Results

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Haplotype analysis

Haplotype analysis using 14 polymorphic markers from chromosome 1q24-q32 revealed that 30 of the 56 individuals studied (11 affected and 19 unaffected) shared a common haplotype over an approximately 12.5-cM interval encompassed between D1S202 and D1S306 (Fig. 1). Thus, the haplotype (6, 3, 9, 7, 1, 10, 11) defined by the seven loci, cen-D1S222, D1S428, D1S422, D1S412, D1S413, D1S2853, D1S2622-tel, respectively, was found in all the 11 affected members from the six families and in 19 of their asymptomatic relatives (Fig. 1). The markers outside this stretch were recombinant in some individuals. These results indicate that these six Roma families are very likely to be related through a recent common ancestor. In contrast, the findings of the haplotype in common between affected and unaffected subjects would indicate an unlikely involvement of genes from this region. The exception to this would be if there was nonpenetrance of the mutant gene in these HPT-JT families. We considered the latter to be more likely, and as the HRPT2 gene is located between the loci D1S422 and D1S412, we explored the possibility that these six Roma families had the same mutation as the cause of their HPT-JT.

DNA sequence analysis

DNA sequence analysis of the HRPT2 gene revealed the same mutation, which consisted of a 2-bp deletion in exon 8, which could be either a TG deletion involving codons 255 and 256 or a GT deletion involving codon 256, in the probands from each of the six HPT-JT families (Figs. 1 and 2). This mutation is predicted to lead to a frameshift that encodes nine missense amino acids, followed by a premature stop at codon 265 (Fig. 2A). The mutation, which involves evolutionarily conserved codons, was also confirmed by ASO hybridization analysis and was shown to cosegregate with the disease in the six Roma families (Figs. 1 and 2). The absence of this 2-bp frameshift deletion in 162 alleles from 81 unrelated, normal individuals, of whom 26 were of Roma origin, demonstrated that this abnormality was a mutation and not a common polymorphism that would be expected to occur in more than 1% of the population. In addition, the mutation was found in the 19 asymptomatic individuals who had the affected haplotype (Fig. 1). These 19 asymptomatic carriers were all normocalcemic with normal serum PTH concentrations and did not have jaw tumors on clinical assessment, which was confirmed radiologically in five cases (Fig. 1). Furthermore, nine of the 19 asymptomatic carriers underwent renal ultrasound, and none of these had significant HPT-JT-related renal abnormalities (Fig. 1). The occurrence of this deletional mutation in these 19 asymptomatic individuals suggests that the mutation is nonpenetrant in some individuals. No mutations were found in the remaining 26 unaffected individuals from these Roma families.

View larger version (40K): [in this window] [in a new window]   FIG. 2. Detection of the mutation of the HRPT2 gene in family 2. DNA sequence analysis revealed a mutation that consisted of a 2-bp deletion in exon 8, which could be either a TG deletion involving codons 255 and 256 or a GT deletion involving codon 256 (DNA sequence chromatogram available on request). This is predicted to result in a frameshift that encodes nine missense amino acids, followed by a premature stop at codon 265 (A). The cosegregation of this mutation with HPT-JT was demonstrated by ASO hybridization analysis (B). The wild-type and mutant alleles are designated + and –, respectively. Individuals are represented using the symbols described in Fig. 1. This mutation was identified in all the 11 affected individuals (see Fig. 1 and Table 1) from the six Roma families and also in 19 unaffected relatives (see Fig. 1).

The nonpenetrance of the deletional mutation of the HRPT2 gene was examined further in relation to age and gender of the individuals. This revealed that the mean age ± SD (34 ± 18) and age range (12–74 yr) of the 19 asymptomatic individuals who harbored the mutation were similar to those of the 11 individuals who also harbored the mutation but had manifestations of HPT-JT (mean age ± SD, 32 ± 17; age range, 14–67 yr). Thus, it appears that the mutation of the HRPT2 gene in these six Roma families has a low penetrance of approximately 37% by the age of 74 yr. A low penetrance of HPT-JT has also been reported in other families (14, 16), and it has been suggested that this may be influenced by gender. Analysis of the male/female ratio among the affected Roma individuals revealed fewer males showing manifestations of HPT-JT, although this did not reach statistical significance (0.6:1; P = 0.30). Additional studies of such HPT families are needed to demonstrate a gender effect in HPT-JT penetrance.

	Discussion

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Our results, which have identified a novel frameshift deletional germline mutation of the HRPT2 gene in six Roma families with HPT-JT from Portugal, demonstrate three important findings related to this recently identified gene (18). First, the mutation represents the first germline abnormality to be identified in exon 8 of this gene. To date, 16 germline mutations have been reported; 44% of these occur in exon 1, and 19% occur in exon 7, with the remainder occurring in exons 2–5 and 14. Furthermore, 56% of these mutations are frameshift deletions involving deletions of 1, 2, 7, or 15 bp (18, 19). Second, the identification of this 2-bp frameshift deletion in all six Roma HPT-JT families together with the demonstration of a shared affected haplotype, ascertained by seven chromosome 1q24-q32 polymorphic loci that span an approximately 12.5-cM region, provide strong support for a founder mutation and, hence, a common ancestry among these families. There are approximately 50,000 individuals of Roma origin in Portugal, and our finding of a founder mutation that appears to have occurred more than three generations ago suggests that additional families are likely to be affected and that targeting an initial search for this 2-bp frameshift deletion may be worthwhile. This search could be performed by either DNA sequence analysis or ASO hybridization analysis depending upon the expertise of the diagnostic laboratory. Furthermore, the Roma population is known to have migrated to other European regions, and thus it is possible that this 2-bp frameshift deletion may be a cause of HPT-JT in other Roma patients. Third, this 2-bp frameshift deletion was also identified in 19 relatives who were asymptomatic, thereby indicating that the mutation has a low age-related penetrance in these families. Nonpenetrance of HPT-JT has been reported in HPT-JT families, but it has not been previously possible to estimate its frequency, as the numbers of individuals in the families studied have been small (14, 16). Our findings, which revealed nonpenetrance of the mutation in 19 of 30 mutant carriers whose age ranged from 12–74 yr, indicate an overall age-related penetrance of approximately 37% by the age of 74 yr. This contrasts markedly with the age-related penetrance of MEN1, another hereditary hyperparathyroid syndrome, which has an age-related penetrance of more than 98% by 40 yr of age (30). However, the estimate for the age-related penetrance for the HRPT2 gene mutation provided by our study requires cautious interpretation, because it is based on a small number of individuals and relates to only one common mutation in one population, which may harbor particular genetic modifiers that could alter the penetrance of the mutation. Gender may alter the expression of the disease-causing mutations, and although our analysis of the male/female ratios could not establish this to be statistically significant, it is nevertheless noteworthy that there are fewer male mutant carriers who show manifestations of HPT-JT. In summary, we report a founder mutation of the HRPT2 gene that is associated with the HPT-JT syndrome in Roma families from Portugal, in whom there appears to be a low age-related penetrance for HPT-JT manifestations.

	Footnotes

 
This work was supported by Fundação Calouste Gulbenkian, Lisboa, Portugal (to V.L. and B.M.C.); Liga Portuguesa Contra o Cancro, Núcleo Regional Sul, Instituto Português de Oncologia de Francisco Gentil-C.R.O.L, S.A. (to B.M.C.); and the Medical Research Council, United Kingdom (to K.J.B., B.H., and R.V.T.).

K.J.B is a Medical Research Council Clinical Training Fellow.

Abbreviations: ASO, Allele-specific oligonucleotide; HPT-JT, hyperparathyroidism-jaw tumor; MEN, multiple endocrine neoplasia.

Received June 11, 2003.

Accepted January 13, 2004.

	References

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1. Aurbach G, Marx S, Spiegel A 1992 Parathyroid hormone, calcitonin and the calciferols. In: Wilson JD, Foster D, eds. Textbook of endocrinology, 7th Ed. Philadelphia: Saunders; 1397–1476
2. Heath H, Hobbs M 1996 Familial hyperparathyroid syndromes. In: Favus MJ, eds. Primer on metabolic bone disorders and disorders of mineral metabolism, 3rd Ed. Philadelphia: Lippincott-Raven; 187–189
3. Thakker RV, Ponder BAJ 1988 Multiple endocrine neoplasia. In: Sheppard MC, eds. Molecular biology and endocrinology. London: Bailliere Tindall; 1031–1067
4. Mulligan LM, Ponder BA 1995 Genetic basis of endocrine disease: multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 80:1989–1995[CrossRef][Medline]
5. Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O’Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV 1996 Clinical studies of multiple endocrine neoplasia type 1 (MEN1). Q J Med 89:653–669
6. Marx SJ 1998 Multiple endocrine neoplasia type 1. In: Vogelstein B, eds. The genetic basis of human cancer. New York: McGraw-Hill; 489–506
7. Thakker RV 2001 Multiple endocrine neoplasia. Horm Res 56:67–72[CrossRef]
8. Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ 2002 Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine 81:1–26[CrossRef][Medline]
9. Jackson CE, Norum RA, Boyd SB, Talpos GB, Wilson SD, Taggart RT, Mallette LE 1990 Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 108:1006–1012[Medline]
10. Szabo J, Heath B, Hill VM, Jackson CE, Zarbo RJ, Mallette LE, Chew SL, Besser GM, Thakker RV, Huff V, Leppert MF, Heath III H 1995 Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21–q31. Am J Hum Genet 56:944–950.[Medline]
11. Teh BT, Farnebo F, Kristoffersson U, Sundelin B, Cardinal J, Axelson R, Yap A, Epstein M, Heath III H, Cameron D, Larsson C 1996 Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21–q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab 81:4204–4211[Abstract]
12. Cavaco BM, Barros L, Pannett AA, Ruas L, Carvalheiro M, Ruas MMA, Krausz T, Santos MA, Sobrinho LG, Leite V, Thakker RV 2001 The hyperparathyroidism-jaw tumor syndrome in a Portuguese kindred. Q J Med 94:213–222
13. Teh BT, Farnebo F, Twigg S, Hoog A, Kytola S, Korpi-Hyovalti E, Wong FK, Nordenstrom J, Grimelius L, Sandelin K, Robinson B, Farnebo LO, Larsson C 1998 Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21–q32 in a subset of families. J Clin Endocrinol Metab 83:2114–2120[Abstract/Free Full Text]
14. Wassif WS, Farnebo F, Teh BT, Moniz CF, Li FY, Harrison JD, Peters TJ, Larsson C, Harris P 1999 Genetic studies of a family with hereditary hyperparathyroidism-jaw tumor syndrome. Clin Endocrinol (Oxf) 50:191–196[CrossRef][Medline]
15. Hobbs MR, Pole AR, Pidwirny GN, Rosen IB, Zarbo RJ, Coon H, Heath III H, Leppert M, Jackson CE 1999 Hyperparathyroidism-jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Am J Hum Genet 64:518–525[CrossRef][Medline]
16. Haven CJ, Wong FK, van Dam EW, van der Juijt R, van Asperen C, Jansen J, Rosenberg C, de Wit M, Roijers J, Hoppener J, Lips CJ, Larsson C, Teh BT, Morreau H 2000 A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 85:1449–1454[Abstract/Free Full Text]
17. Kakinuma A, Morimoto I, Nakano Y, Fujimoto R, Ishida O, Okada Y, Inokuchi N, Fujihira T, Eto S 1994 Familial primary hyperparathyroidism complicated with Wilms’ tumor. Intern Med 33:123–126[Medline]
18. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hoog A, Heath III H, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR 2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32:676–680[CrossRef][Medline]
19. Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT 2003 HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 40:657–663[Abstract/Free Full Text]
20. Solcia E, Klöppel G, Sobin LH 2000 Tumours of the parathyroid glands. In: WHO, eds. Histological typing of endocrine tumours, 2nd Ed. New York: Springer; 48–56
21. DeLellis RA 1993 Tumors of the parathyroid gland. In: Rosai J, eds. Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology; 53–63
22. Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK, Besser GM, O’Riordan JL 1989 Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 321:218–224[Abstract]
23. Shibata D 1994 Extraction of DNA from paraffin-embedded tissue for analysis by polymerase chain reaction: new tricks from an old friend. Hum Pathol 25:561–563[CrossRef][Medline]
24. Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN, Thakker RV 1996 Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumours. Clin Endocrinol (Oxf) 45:195–200[CrossRef][Medline]
25. Pang JT, Lloyd SE, Wooding C, Farren B, Pottinger B, Harding B, Leigh SE, Pook MA, Benham FJ, Gillett GT, Taggart RT, Thakker RV 1996 Genetic mapping studies of 40 loci and 23 cosmids in chromosome 11p13–11q13, and exclusion of µ-calpain as the multiple endocrine neoplasia type 1 gene. Hum Genet 97:732–741[Medline]
26. Pannett AAJ, Thakker RV 2001 Somatic mutations in MEN type 1 tumors, consistent with the Knudson "two-hit" hypothesis. J Clin Endocrinol Metab 86:4371–4374[Abstract/Free Full Text]
27. Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M Clayton RN 1993 Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest 91:2815–2821
28. Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA 1994 Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 3:1303–1308[Abstract/Free Full Text]
29. Pannett AA, Kennedy AM, Turner JJ, Forbes SA, Cavaco BM, Bassett JH, Cianferotti L, Harding B, Shine B, Flinter F, Maidment CG, Trembath R, Thakker RV 2003 Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 58:639–646[CrossRef][Medline]
30. Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV 1998 Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62:232–244[CrossRef][Medline]

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