Table 2.
Mutations observed in the human fumarase gene and association to disease. Abbreviations: CL: cutaneous leiomyoma; FHD: fumarate hydratase deficiency; HLRCC: hereditary leiomyomatosis and renal cell cancer; LCT: Leydig cell tumors; MCUL: multiple cutaneous and uterine leiomyomata; OMC: ovarian mucinous cystadenoma; RCC: renal cell carcinoma; STS: soft tissue sarcoma; UL: uterine leiomyomas; ULMS: uterine leiomyosarcoma
| # | Mutation site | Mutated residue | Protein change | DNA change | Exon | Conservation | Localization | Reference | Phenotype |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Arg51 | Glu | R51E | c.152 G > A | 2 | Conserved | Surface | (Kiuru et al. 2002) | STS |
| 2 | Arg101 | Pro | R101P | c.302 G > C | 3 | Semi-conserved | Surface | (Chan et al. 2005), (Heinritz et al. 2008) | HLRCC |
| 3 | Asn107 | Thr | N107T | c.320A > C | 3 | Conserved | Active site | (Tomlinson et al. 2002), (Alam et al. 2005a), (Carvajal-Carmona et al. 2006) | MCUL, LCT |
| 4 | Ala117 | Pro | A117P | c.349 G > C | 3 | Semi-conserved | Near active site | (Tomlinson et al. 2002) | MCUL |
| 5 | Leu132 | Ser | L132S | c.395 T > C | 4 | Semi-conserved | Surface | (Wei et al. 2006) | HLRCC, reduced FH activity |
| 6 | His135 | Arg | H135R | c.404A > G | 4 | Semi-conserved | Surface | (Chuang et al. 2005) | MCUL |
| 7 | Gln142 | Lys | Q142K | c.424 C > A | 4 | Conserved | Near active site | (Badeloe et al. 2006) | MCUL |
| 8 | Ser158 | Ile | S158I | c.473 G > T | 4 | Semi-conserved | Near active site | (Martinez-Mir et al. 2003) | MCUL |
| 9 | Arg160 | Gly | R160G | c.478A > G | 4 | Conserved | Surface | (Wei et al. 2006) | MUCL, reduced FH activity |
| 10 | Pro174 | Arg | P174R | c.521 C > G | 4 | Not conserved | Surface | (Alam et al. 2005b), (Zeng et al. 2006), (Pollard et al. 2005) | FHD |
| 11 | His180 | Arg | H180R | c.539A > G | 4 | Semi-conserved | Active site | (Tomlinson et al. 2002), (Alam et al. 2005b) | MUCL |
| 12 | Gln185 | Arg | Q185R | c.554A > G | 4 | Conserved | Active site | (Tomlinson et al. 2002) | MCUL |
| 13 | Ser187 | Leu | S187L | c.560C > T | 5 | Conserved | Active site | (Toro et al. 2003) | MCUL |
| 14 | Asn188 | Ser | N188S | c.563A > G | 5 | Conserved | Active site | (Toro et al. 2003) | MCUL |
| 15 | Pro192 | Leu | P192L | c.575A > G | 5 | Conserved | In core helice | (Chuang et al. 2005) | MCUL |
| 16 | Met195 | Thr | M195T | c.584 T > C | 5 | Conserved | In core helice | (Toro et al. 2003) | MCUL |
| 17 | His196 | Arg | H196R | c.587A > G | 5 | Conserved | In core helice | (Kiuru et al. 2002), (Lehtonen et al. 2004) | RCC, ULMS |
| 18 | Ile229 | Thr | I229T | c.686 T > C | 5 | Not conserved | Surface | (Alam et al. 2005b) | MCUL |
| 19 | Lys230 | Arg | K230R | c.689A > G | 5 | Conserved | Subunit stabilization | (Tomlinson et al. 2002), (Coughlin et al. 1998), (Manning et al. 2000) | FHD |
| 20 | Arg233 | Cys | R233C | c.697 C > T | 5 | Conserved | Active site | (Rustin et al. 1997), (Chuang et al. 2005), (Wei et al. 2006) | FHD, HLRCC, MCUL |
| 21 | Arg233 | His | R233H | c.698 G > A | 5 | Conserved | Active site | (Tomlinson et al. 2002), (Alam et al. 2005b), (Wei et al. 2006), (Chuang et al. 2005), (Toro et al. 2003) | HLRCC, MCUL |
| 22 | Arg233 | Leu | R233L | c.698 G > T | 5 | Conserved | Active site | (Chuang et al. 2005), (Toro et al. 2003) | MCUL |
| 23 | Ala239 | Thr | A239T | c.715 G > A | 5 | Conserved | Near active site | (Lehtonen et al. 2004) | UL |
| 24 | Ala274 | Thr | A274T | c.820 G > A | 6 | Not conserved | Active site | (Ylisaukko-oja et al. 2006) | OMC |
| 25 | Gly282 | Val | G282V | c.845 G > T | 6 | Conserved | Active site | (Tomlinson et al. 2002), (Alam et al. 2005b) | MCUL |
| 26 | Ala308 | Thr | A308T | c.922 G > A | 7 | Conserved | Surface | (Coughlin et al. 1998) | FHD |
| 27 | Asn310 | Tyr | N310Y | c.928A > T | 7 | Conserved | Surface | (Alam et al. 2005b) | MCUL |
| 28 | Phe312 | Cys | F312C | c.935 T > G | 7 | Conserved | Surface | (Coughlin et al. 1998) | FHD |
| 29 | His318 | Tyr | H318Y | c.952 C > T | 7 | Semi-conserved | In core helice | (Toro et al. 2003), (Martinez-Mir et al. 2003) | HLRCC |
| 30 | His318 | Leu | H318L | c.953A > T | 7 | Semi-conserved | In core helice | (Deschauer et al. 2006) | FHD |
| 31 | Val322 | Asp | V322D | c.964 T > A | 7 | Conserved | In core helice (interaction with 1 other monomer) | (Toro et al. 2003) | MCUL |
| 32 | Thr330 | Pro | T330P | c.988A > C | 7 | Semi-conserved | In core helice (interaction with 1 other monomer) | (Chuang et al. 2005) | MCUL |
| 33 | Cys333 | Tyr | C333Y | c.998 G > A | 7 | Semi-conserved | In core helice (interaction with 1 other monomer) | MCUL | |
| 34 | Ser334 | Arg | S334R | c.1002 T > G | 7 | Conserved | In core helice (interaction with 1 other monomer) | (Badeloe et al. 2006) | CL |
| 35 | Leu335 | Pro | L335P | c.1004 T > C | 7 | Conserved | In core helice | (Toro et al. 2003) | MCUL |
| 36 | Asn340 | Lys | N340K | c.1020 T > A | 7 | Semi-conserved | In core helice | (Toro et al. 2003), (Wei et al. 2006) | MCUL |
| 37 | Glu355 | Lys | E355K | c.1063 G > A | 7 | Conserved | Subunit stabilization | (Alam et al. 2005b) | MCUL |
| 38 | Asn361 | Lys | N361K | c.1083 T > A | 7 | Conserved | Active site | (Alam et al. 2005b) | HLRCC-CDC |
| 39 | Glu362 | Gln | E362Q | c.1084 G > C | 7 | Conserved | Active site | (Bourgeron et al. 1994) | FHD |
| 40 | Ser365 | Gly | S365G | c.1093 G > A | 7 | Conserved | Active site | (Toro et al. 2003), (Wei et al. 2006) | MCUL |
| 41 | Ser366 | Asn | S366N | c.1097 G > A | 7 | Conserved | Active site (but out) | (Toro et al. 2003), (Alam et al. 2005b) | MCUL |
| 42 | Met368 | Thr | M368T | c.1103 T > C | 7 | Conserved | Active site | (Badeloe et al. 2006) | MCUL |
| 43 | Pro369 | Ser | P369S | c.1105 C > T | 7 | Conserved | Active site (but out) | (Maradin et al. 2006) | FHD |
| 44 | Asn373 | Ser | N373S | c.1118A > G | 8 | Conserved | Active site | (Lehtonen et al. 2004) | HLRCC/clear cell RCC |
| 45 | Gln376 | Pro | Q376P | c.1127A > C | 8 | Conserved | In core helice (interaction with 1 other monomer) | (Zeman et al. 2000), (Remes et al. 2004), (Phillips et al. 2006) | FHD |
| 46 | Ala385 | Asp | A385D | c.1154 C > A | 8 | Not conserved | In core helice (interaction with 2 other monomers) | (Wei et al. 2006) | MCUL |
| 47 | Val394 | Leu | V394L | c.1180 G > C | 8 | Not conserved | In core helice | (Martinez-Mir et al. 2003) | MCUL |
| 48 | Gly397 | Arg | G397R | c.1189 G > A | 8 | Semi- conserved | In core helice | (Alam et al. 2005b) | MCUL |
| 49 | His402 | Cys | H402C | c.1207 C > T | 8 | Conserved | In core helice turn (interaction with 2 other monomers) | (Phillips et al. 2006) | FHD |
| 50 | Ser419 | Pro | S419P | c.1255 T > C | 9 | Conserved | In core helice | (Wei et al. 2006) | HLRCC |
| 51 | Asp425 | Val | D425V | c.1274A > T | 9 | Conserved | In core helice (interaction with 1 other monomer) | (Coughlin et al. 1998) | FHD |
| 52 | Gln439 | Pro | Q439P | c.1316A > C | 9 | Not conserved | Surface | (Wei et al. 2006) | HLRCC |
| 53 | Met454 | Ile | M454I | c.1362 G > A | 9 | Conserved | Subunit interaction | (Carvajal-Carmona et al. 2006) | LCT |
| 54 | Tyr465 | Cys | Y465C | c.1394A > G | 10 | Semi- conserved | Surface | (Toro et al. 2003) | MCUL |
| 55 | Leu507 | Pro | L507P | c.1520 T > C | 10 | Semi- conserved | Surface near opening active site | (Alam et al. 2005b) | MCUL |