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Supplementary Table 2 MEN1, HRPT2 and CASR germline mutations detected in patients with FIHP.
Gene
Mutation
typea
Exon
Codon
Predicted effect
References
(see below)
2
83–84
Frameshift, premature stopc
6
3
177–178
17
7
350
19
8
353
20
8
363
Frameshift, premature stop at codon
183
Frameshift, premature stop at codon
365
Frameshift, premature stop at codon
407
Inframe deletion of Glu363
23
9
414
Inframe deletion of Leu414
26
10
458–459
Frameshift, premature stopc
28
10
553
Frameshift, premature stopc
29
10
559
Frameshift, premature stop at codon
561
Karges et al.
(2000)25
Pannett et al.
(2003)26
Pannett et al.
(2003)26
Warner et al.
(2004)27
Miedlich et al.
(2001)28
Sato et al.
(1998)29
Takami et al.
(2000)30
Villablanca et
al. (2002)31
Cetani et al.
(2002)32
2
85–86
3
2
86
Frameshift, premature stop at codon
121
Inframe insertion of 6 amino acids
27
10
515–516
Frameshift, premature stop at codon
529
Nonsense
21
8
366
Glu366Stop
Takami et al.
(2000)30
Missense
4
2
112
Leu112Val
5
3
153
Asp153Val
7
3
184
Val184Glu
8
3
197
Thr197Ile
9
4
220
Trp220Leu
10
4
225
Gly225Arg
11
4
255
Glu255Lys
12
4
260
Gln260Pro
14
5
267
Leu267Pro
16
7
305
Gly305Asp
18
8
351
Tyr351Asn
22
9
411
Ala411Pro
24
9
418
Asp418His
Villablanca et
al. (2002)31
Pannett et al.
(2003)26
Fujimori et al.
(1998)34
Warner et al.
(2004)27
This study
(Figure 1)
Mizusawa et al.
(2006)35
Teh et al.
(1998)36
Kassem et al.
(2000)37
Poncin et al.
(1999)38
Honda et al.
(2000)39
This study
(Figure 1)
Pannett et al.
(2003)26
Warner J et al.
(2004)27;
Cetani et al.
(2006)40
MEN1
Intragenic
deletion
1
Intragenic
insertion
2
Warner et al.
(2004)27
Bergman et al.
(2000)33
Warner et al.
(2004)27
Supplemantary table 2 Continued.
Gene
Mutation
typea
Exon
Codon
Predicted effect
Referencee
Boundary
between intron 4
and exon 5
Boundary
between exon 5
and intron 5
Boundary
between exon 9
and intron 9
Nucleotide
806–9b
Acceptor splice-site alterationd
Cetani et al.
(2006)40
Nucleotide
847+1b
Donor splice-site alterationd
Cetani et al.
(2006)40
Nucleotide
1350+1b
Donor splice-site alterationd
Carrasco CA et
al. (2004)42
1
21–22
Frameshift, premature stopd
2
47–48
7
172–173
Frameshift, premature stop at codon
62
Frameshift, premature stopd
7
229
Frameshift, premature stop at codon
254
Mizusawa et al.
(2006)35
Kelly et al.
(2006)42
Mizusawa et al.
(2006)35
Guarnieri et al.
(2006)43
7
226
Frameshift, premature stop at codon
229
Simonds et al.
(2004)44
8
248
Frameshift, premature stop at codon
265
Bradley et al.
(2006)45
2
64
Leu64Pro
Villablanca et
al. (2004)46
Boundary
between exon 1
and intron 1
Nucleotide
131+1b
Donor splice-site alterationd
Boundary
between exon 2
and intron 2
Nucleotide
237+1b
Donor splice-site alterationd
Cetani F et al.
(2004)47;
Bradley et al.
(2005)48
Villablanca et
al. (2004)46
4
336
Inframe deletion of Lys336
Warner et al.
(2004)27
3
100
Thr100Ile
7
650
Leu 650Pro
7
689
Val689Met
7
881
Phe881Leu
Warner et al.
(2004)27
Warner et al.
(2004)27
Warner et al.
(2004)27
Carling et al.
(2000)49
MEN1
Splice-site
13
15
25
HRPT2
Intragenic
deletion
Intragenic
insertion
Missense
Splice-site
CASR
Intragenic
deletion
Missense
Abbreviations: CASR, calcium-sensing receptor gene; FIHP, familial isolated hyperparathyroidism; HRPT2,
hyperparathyroidism 2 gene; MEN1, multiple endocrine neoplasia type 1 gene. aMutation number and symbol
refers to location shown in Supplementary Figure 2. bNucleotide positions start from initiation codon. cLocation of
premature stop codon not known. dPredicted to lead to protein truncation.
References
25 Karges W et al. (2000) Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with
sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region .
J Endocrinol 166: 1–9
26 Pannett AA et al. (2003) Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated
primary hyperparathyroidism. Clin Endocrinol (Oxf) 58: 639–646
27 Warner J et al. (2004) Genetic testing in familial isolated hyperparathyroidism: unexpected results and their
implications. J Med Genet 41: 155–160
28 Miedlich S et al. (2001) Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1
variant? Eur J Endocrinol 145: 155–160
29 Sato M et al. (1998) Identification of five novel germline mutations of the MEN1 gene in Japanese multiple
endocrine neoplasia type 1 (MEN1) families. J Med Genet 35: 915–919
30 Takami H et al. (2000) Familial hyperparathyroidism. Biomed Pharmacother 54 (Suppl 1): 21s–24s
31 Villablanca A et al. (2002) Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur
J Endocrinol 147: 313–322
32 Cetani F et al. (2002) Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with
familial isolated hyperparathyroidism. Clin Endocrinol (Oxf) 56: 457–464
33 Bergman L et al. (2000) Identification of MEN1 gene mutations in families with MEN 1 and related disorders.
Br J Cancer 83: 1009–1014
34 Fujimori M et al. (1998) Novel V184E MEN1 germline mutation in a Japanese kindred with familial
hyperparathyroidism. Am J Med Genet 80: 221–222
35 Mizusawa N et al. (2006) Genetic analyses in patients with familial isolated hyperparathyroidism and
hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf) 65: 9–16
36 Teh BT et al. (1998) A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and
showing loss of the wild-type alleles in the parathyroid tumors. Am J Hum Genet 63: 1544–1549
37 Kassem M et al. (2000) Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia
type 1 in a large Danish pedigree. J Clin Endocrinol Metab 85: 165–167
38 Poncin J et al. (1999) Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine
neoplasia type 1 and related diseases. Hum Mutat 13: 54–60
39 Honda M et al. (2000) A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated
primary hyperparathyroidism. Eur J Endocrinol 142: 138–143
40 Cetani F et al. (2006) Genetic analyses in familial isolated hyperparathyroidism: implication for clinical
assessment and surgical management. Clin Endocrinol (Oxf) 64: 146–152
41 Carrasco CA et al. (2004) Novel intronic mutation of MEN1 gene causing familial isolated primary
hyperparathyroidism. J Clin Endocrinol Metab 89: 4124–4129
42 Kelly TG et al. (2006) Surveillance for early detection of aggressive parathyroid disease: carcinoma and
atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. J Bone
Miner Res 21: 1666–1671
43 Guarnieri V et al. (2006) Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with
HRPT2 mutation: implications for cancer surveillance. J Clin Endocrinol Metab 91: 2827–2832
44 Simonds WF et al. (2004) Familial isolated hyperparathyroidism is rarely caused by germline mutation in
HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 89: 96–102
45 Bradley KJ et al. (2006) Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid
tumours. Clin Endocrinol (Oxf) 64: 299–306
46 Villablanca A et al. (2004) Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial
isolated hyperparathyroidism (FIHP). J Med Genet 41: e32
47 Cetani F et al. (2004) Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and
somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 89: 5583–5591
48 Bradley KJ et al. (2005) Utilisation of a cryptic non-canonical donor splice site of the gene encoding
PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. J Med Genet 42: e51
49 Carling T et al. (2000) Familial hypercalcemia and hypercalciuria caused by a novel mutation in the
cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 85: 2042–2047