Table 4.
Summary of CDC73, MEN1, and CASR mutations associated with familial isolated primary hyperparathyroidism
| Mutation a | Exon/intron | Codon b | Predicted effect c | Type d | Original designation | References |
|---|---|---|---|---|---|---|
| CDC73 | ||||||
| c.61_64del | Exon 1 | 21 | p.Lys21GlufsX4 | S1 | c.61_64del4 | Kelly et al. (2006) |
| c.62_66del | Exon 1 | 21 | p.Lys21ArgfsX43 | G | 62–66del | Mizusawa et al. (2006) |
| c.70_73del | Exon 1 | 24 | p.Glu24X | S2 | 70–73del | Mizusawa et al. (2006) |
| c.95_102del | Exon 1 | 32 | p.Trp32X | S2 | 95–102del | Mizusawa et al. (2006) |
| c.128G > A | Exon 1 | 43 | p.Trp43X | S | 128G→A | Carpten et al. (2002)q |
| c.131+1G > A | Intron 1 | splice [d]n | G | IVS1+1G > A | Cetani et al. (2004) | |
| c.131+1G > A | Intron 1 | splice [d]n | G | IVS1+1 g→a | Bradley et al. (2005a) | |
| c.140_144del | Exon 2 | 47 | p.Lys47ArgfsX17 | Go ,1 | c.140_144del5 | Kelly et al. (2006) |
| c.157G > T | Exon 2 | 53 | Glu53X | G | c.157G > T (Glu53X) | Kong et al. (2014) |
| c.188T > C | Exon 2 | 63 | p.Leu63Pro | G | c.188T > C | Newey et al. (2010) |
| c.191T > C | Exon 2 | 64 | p.Leu64Pro | G | 191T→C | Villablanca et al. (2004) |
| c.194dup | Exon 2 | 65 | p.Asn65LysfsX2 | G | 194dupA | Takeuchi et al. (2015) |
| c.205dup | Exon 2 | 69 | p.Leu69ProfsX13 | Go | c.205dupC | Pichardo‐Lowden et al. (2011)e |
| c.237+1G > C | Intron 2 | splice [d]n | G | IVS2+1G→C | Villablanca et al. (2004)n (rt) | |
| c.253_258del | Exon 3 | 85 | p.Val85_Val86del | G | c.252_257del6 | Pazienza et al. (2013) |
| c.272G > C | Exon 3 | 91 | p.Arg91Pro | Go | Arg91Pro | Zhang et al. (2012)f |
| c.284T > C | Exon 3 | 95 | p.Leu95Pro | So ,3 | c.284T > C | Yu et al. (2015)g |
| c.293T > C | Exon 3 | 98 | p.Leu98Pro | G | c.293T > C exon 3 | Bricaire et al. (2013)n (ut) |
| c.307+1G > A | Intron 3 | splice [d] | Go | IVS3+1 G > A | Kong et al. (2014) | |
| c.308–9T > A | Intron 3 | splice [vus] | G | c.308–9T > A intron 3 | Bricaire et al. (2013)n (rt,jt?) | |
| c.343G > T | Exon 4 | 115 | p.Glu115X | Go | c.343G > T | Guarnieri et al. (2008)h |
| c.356del | Exon 4 | 119 | p.Gln119ArgfsX14 | Go ,3 | 356delA | Bradley et al. (2006)g |
| c.415C > T | Exon 5 | 139 | p.Arg139X | Go | c.415C > T | Guarnieri et al. (2008)h , i , n (rt,ut) |
| c.483_486del | Exon 6 | 162 | p.Glu162GlyfsX39 | G | c.481_484delAAAG exon 6 | Bricaire et al. (2013)n (ut,jt?) |
| c.505C > T | Exon 6 | 169 | p. Gln169X | G | c.505C > T | Ghemigian et al. (2013) |
| c.520_523del | Exon 7 | 174 | p.Ser174LysfsX27 | Go | c.518_521delTCTC | Guarnieri et al. (2008)h,i,n(rt,ut) |
| c.520_523del | Exon 7 | 174 | p.Ser174LysfsX27 | G2 | 518–521del | Mizusawa et al. (2006) |
| c.664C > T | Exon 7 | 222 | p.Arg222X | G | R222X | Khadilkar et al. (2015) |
| c.664C > T | Exon 7 | 222 | p.Arg222X | G | c.664 C > T (Arg222X) | Kong et al. (2014) |
| c.679_680insAG | Exon 7 | 227 | p.Arg227LysfsX31 | Go | 679_680insAG | Simonds et al. (2004)n (lip) |
| c.685_688del | Exon 7 | 229 | p.Arg229TyrfsX27 | Go | 685delAGAG | Guarnieri et al. (2006)n (rt,ut) |
| c.745dup | Exon 8 | 249 | p.Ile249AsnfsX18 | G | 745 dup 1 bp | Bradley et al. (2006) |
| Gross deletion | G | c.237‐?_308‐?del exon 3 | Bricaire et al. (2013)n (rt,jt?) | |||
| Gross deletion | G | c.131 ?_308‐?del exons 2–3 | Bricaire et al. (2013) | |||
| Gross deletion | Go | Deletion exon 1–10 | Korpi‐Hyovalti et al. (2014)n (rt) | |||
| MEN1 | ||||||
| c.13_15delinsACGCT | Exon 2 | 5 | p.Ala5ThrfsX115 | G | 13insACGCTdelGCC | Cardinal et al. (2005)i |
| c.249_252del | Exon 2 | 85 | p.Ile85SerfsX33 | G | 249del4 | Karges et al. (2000) |
| c.255_256insCAGTGGCCGACCTGTCTAT | Exon 2 | 86 | p.Ile86GlnfsX37 | G | 2543ins18 | Bergman et al. (2000)i, j |
| c.255_256insCAGTGGCCGACCTGTCTAT | Exon 2 | 86 | p.Ile86GlnfsX37 | G | c.255_256insCAGTGGCCGACCTGTCTAT | Warner et al. (2004)i |
| c.255_256insCAGTGGCCGACCTGTCTAT | Exon 2 | 86 | p.Ile86GlnfsX37 | G | 255ins19 | Cardinal et al. (2005)i |
| c.334G > C | Exon 2 | 112 | p.Val112Leu | G | L112V | Villablanca et al. (2002) |
| c.458A > T | Exon 3 | 153 | Asp153Val | G | D153V | Pannett et al. (2003) |
| c.532_535del | Exon 3 | 178 | p.Ser178ArgfsX6 | G | codon 177–178(delGTCT) | Pannett et al. (2003) |
| c.551T > A | Exon 3 | 184 | p.Val184Glu | G | V184E | Fujimori et al. (1998) |
| c.590C > T | Exon 3 | 197 | p.Thr197Ile | G | 590C > T | Warner et al. (2004)i |
| c.590C > T | Exon 3 | 197 | p.Thr197Ile | G | 590C→T | Cardinal et al. (2005)i |
| c.600_601dup | Exon 3 | 201 | p.Lys201ThrfsX24 | G | 711dupCA | Wautot et al. (2002)k |
| c.654G > Tp | Exon 3 | 218 | G | codon 219 (CGG→CGT) | Dwarakanathan, Zwart and Oathus (2000) | |
| c.659G > T | Exon 4 | 220 | p.Trp220Leu | G | Trp220Leu | Hannan et al. (2008) |
| c.673G > A | Exon 4 | 225 | p.Gly225Arg | G | G225R (GGA→AGA) | Mizusawa et al. (2006) |
| c.722G > T | Exon 4 | 241 | p.Cys241Phe | G | C240F | Wautot et al. (2002)k |
| c.763G > A | Exon 4 | 255 | p.Glu255Lys | G | E255K | Teh et al. (1998) |
| c.779A > C | Exon 4 | 260 | p.Gln260Pro | G | Q260P | Kassem, Kruse, Wong, Larsson and Teh (2000) |
| c.784‐9G > A | Intron 4 | splice [vus] | G | IVS4 ‐9G→A | Cetani et al. (2006)n (rt,lip,tn) | |
| c.800T > C | Exon 5 | 267 | p.Leu267Pro | G | 910T→C | Poncin et al. (1999) |
| c.824G > T | Exon 5 | 275 | p.Arg275Met | G | c.824G > T | Nagamura et al. (2012) |
| c.824+1G > A | Intron 5 | splice [d] | G | IVS5 +1G→A | Cetani et al. (2006)n (lip) | |
| c.914G > A | Exon 7 | 305 | p.Gly305Asp | G | G305D | Honda et al. (2000) |
| c.1021T > C | Exon 7 | 341 | p.Trp341Arg | G | c.T1021C: p.W341R | Isakov et al. (2013) |
| c.1021T > C | Exon 7 | 341 | p.Trp341Arg | G | W341R | Wautot et al. (2002)k |
| c.1049+2_1049+5del | Intron 7 | splice [vus] | G | codon 350 (delGAgt) | Pannett et al. (2003) | |
| c.1051T > A | Exon 8 | 351 | p.Tyr351Asn | G | Tyr351Asn | Hannan et al. (2008) |
| c.1059C > A | Exon 8 | 353 | p.Tyr353X | G | Y353X | Shimizu et al. (1997) |
| c.1058_1060del | Exon 8 | 353 | p.Tyr353del | G | 1057‐1059delACT | Warner et al. (2004)i |
| c.1058_1060del | Exon 8 | 353 | p.Tyr353del | G | 1057‐1060delACT | Cardinal et al. (2005)i |
| c.1069G > C | Exon 8 | 357 | p.Asp357His | G | D357H | Wautot et al. (2002)k |
| c.1087_1089del | Exon 8 | 363 | p.Glu363del | G | E363del | Miedlich, Lohmann, Schneyer, Lamesch and Paschke (2001) |
| c.1096G > T | Exon 8 | 366 | p.Glu366X | G | Q366X | Takami et al. (2000) |
| c.1190_1193del | Exon 9 | 397 | p.Thr397ArgfsX47 | G | 1298del4 | Wautot et al. (2002)k |
| c.1231G > C | Exon 9 | 411 | p.Ala411Pro | G | A411P | Pannett et al. (2003) |
| c.1241_1243del | Exon 9 | 414 | p.Leu414del | G | 1350del3 | Sato et al. (1998) |
| c.1241_1243del | Exon 9 | 414 | p.Leu414del | G | 1350del3 | Ohye et al. (1998) |
| c.1252G > C | Exon 9 | 418 | p.Asp418His | G | 1252G > C | Warner et al. (2004)l |
| c.1252G > C | Exon 9 | 418 | p.Asp418His | G | D418H | Cetani et al. (2006)n (tn) |
| c.1343_1353del | Exon 9 | 448 | p.Glu448AlafsX79 | G | 1452deL11 | Wautot et al. (2002)k |
| c.1350+1G > A | Intron 9 | splice [d] | Go | IVS9 +1G > A | Carrasco et al. (2004)q | |
| c. 1373_1376del | Exon 10 | 458 | p.Val458AlafsX100 | G | 1483del4 | Takami et al. (2000) |
| c.1382_1404del | Exon 10 | 461 | p.Glu461GlyfsX62 | G | 1486del23 | Wautot et al. (2002)k |
| c.1546dup | Exon 10 | 516 | p.Arg516ProfsX15 | G | 1546‐1547insC | Warner et al. (2004) |
| c.1548del | Exon 10 | 516 | p.Lys517SerfsX42 | G | 1658delG | Villablanca et al. (2002) |
| c.1676del | Exon 10 | 559 | p.Lys559ArgfsX3 | G | 1785delA | Cetani et al. (2002) |
| Gross deletion | G | gross deletion | Cebrian et al. (2003) | |||
| CASR | ||||||
| c.299C > T | Exon 3 | 100 | p.Thr100Ile | G | T100I | Warner et al. (2004)n (hca) |
| c.476T > C | Exon 3 | 159 | p.Leu159Pro | G | L159P | Simonds et al. (2002)n (hca,uccr) |
| c.658C > T | Exon 4 | 220 | p.Arg220Trp | G | R220W | Simonds et al. (2002)n (hca,uccr) |
| c.748G > A | Exon 4 | 250 | p.Glu250Lys | G | E250K | Simonds et al. (2002) |
| c.802_812del | Exon 4 | 268 | p.Val268GlnfsX6 | G | V268del‐11 × 273 | Simonds et al. (2002)n (hca,hcu) |
| c.1006_1008del | Exon 4 | 336 | p.Lys336del | G | K336del | Warner et al. (2004)n (hca,hcu) |
| c.1949T > C | Exon 7 | 650 | p.Leu650Pro | G | L650P | Warner et al. (2004)n (hca) |
| c.2065G > A | Exon 7 | 689 | p.Val689Met | G | V689M | Warner et al. (2004)n (hca) |
| c.2641T > C | Exon 7 | 881 | p.Phe881Leu | G | F881L | Carling et al. (2000)n (hca) |
| c.2657G > C | Exon 7 | 886 | p.Arg886Pro | G | R886P | Simonds et al. (2002)n (hca,uccr) |
Mutations are numbered in relation to the cell division cycle 73 (CDC73), multiple endocrine neoplasia type 1 (MEN1), and calcium‐sensing receptor (CASR) cDNA reference sequences (GenBank accession number NM_024529.4, NM_130799.2, NM_000388.3, respectively) whereby nucleotide +1 corresponds to the A of the ATG‐translation initiation codon. All mutations were analyzed using the Leiden Open Variation Database (LOVD) Mutalyzer sequence variant nomenclature checker (https://www.lovd.nl/mutalyzer/) and annotated using the Human Genome Variation Society (HGVS) guidelines (https://www.hgvs.org/).
Codon numbering starts from initiation codon of CDC73, MEN1, and CASR mRNA.
Predicted effect: splice, splice site mutation; [d] donor splice site; [a] acceptor splice site; [vus] variant of unknown significance.
Mutation type: G, germline; S, somatic; ND, not defined. Equal superscript numbers represent germline and/or somatic mutations occurring in the same patient.
It is possible this is a case of HPT‐JT associated with PC since: the patient was diagnosed with three renal cysts, while “a maternal cousin had jaw pain and presumably bone destruction of the jaw, termed a ‘hole in the jaw’.” Furthermore, histological description of the proband's parathyroid gland was consistent with an APA (“…vascular and capsular invasion, but no definitive features of PC were identified”) and disease recurrence on the contra‐lateral side (again with diagnosis of APA) suggests a more malignant behavior.
All mutation carriers (n = 3) of this kindred developed PC.
Kindred originally reported by Williamson et al., and classified as HPT‐JT by Carpten et al. and FIHP by Bradley et al., and associated with PC by Carpten et al., Bradley et al., and Yu et al. (Williamson et al., 1999; Carpten et al., 2002; Bradley et al., 2005a; Bradley et al., 2006; Yu et al., 2015).
Reported as a FIHP family, but no information was provided on the pHPT status of the mutation carriers.
Additional clinical details about these kindreds are provided by Corbetta et al. (2010) and Vaira et al. (2012).
Studies reported by the same group, therefore it is not possible to exclude that equal mutations described in different publications are from the same proband/kindred.
Mutation was incorrectly reported in the original publication and was posteriorly updated by Warner et al. (2004) and Cardinal et al. (2005).
The authors collected 165 MEN1 mutations in patients with MEN1, but seven probands/kindreds exhibited FIHP phenotype (i.e., only pHPT) and were included here.
In a posterior publication, this mutation was identified by the same group in a kindred with MEN1 syndrome, and it is unclear if there were two different kindreds with the same mutation or if it was an update of the previous kindred (Cardinal et al., 2005).
Presence in the probands/kindreds of: rt renal cysts/lesions, and/or ut uterine tumors (if the presence of renal cysts or uterine tumors was unknown, one “?” was added next to the previous superscripts; hjt? was added if the absence of jaw tumors was unknown), and/or lip lipoma, and/or tn thyroid nodules, and/or hca hypercalcemia, and/or hcu hypercalciuria, and/or uccr urine calcium/creatinine clearance ratio < 0.010 in most of the affected individuals.
For detailed information of the effect of CDC73 mutation on splicing please consult Hahn et al. (2009).
Mutations identified in kindreds with case reports of PC.
Discordant codon/nucleotide number in the original report. There is no predicted change on the amino acid (p.Arg218 = ), but the authors reported altered RNA splicing caused by this nucleotide change.
Criteria for diagnosis of PC not reported.
HPT‐JT, hyperparathyroidism‐jaw tumor; PC, parathyroid carcinoma; APA, atypical parathyroid adenoma; FIHP, familial isolated primary hyperparathyroidism; MEN1, multiple endocrine neoplasia type 1.