Table 2.
PROKR2 and PROK2 mutations in Kallmann syndrome.
| Exon | Nucleotide change | Amino acid change | Localization (domain) | Functional consequence | Reference |
|---|---|---|---|---|---|
| PROKR2 | |||||
| 1 | 58del | Frameshift | N-terminal region | NMD or protein truncation | Dodé et al. (2006) |
| 151G > A | A51T | N-terminal region | None? | Reynaud et al. (2012), Sbai et al. (unpublished) | |
| 238C > T | R80C | First intracellular loop | None? | Abreu et al. (2010), Sbai et al. (unpublished) | |
| – | 253C > T | R85C | – | Mild G protein-coupling defect | Cole et al. (2008), Monnier et al. (2009), Sarfati et al. (2010) |
| – | 253C > G | R85G | – | Strong G protein-coupling defect | Sarfati et al. (2010), Raivio et al. (2012) |
| – | 254G > T | R85L | – | Mild protein-coupling defect | Sarfati et al. (2010), Sbai et al. (unpublished) |
| – | 254G > A | R85H | – | Mild G protein-coupling defect | Dodé et al. (2006), Monnier et al. (2009) |
| – | 337T > C | Y113H | First extracellular loop | Strong G protein-coupling defect | Cole et al. (2008), Sbai et al. (unpublished) |
| – | 343G > A | V115M | – | Strong G protein-coupling defect | Cole et al. (2008), Sbai et al. (unpublished) |
| 349C > T | R117W | – | Strong G protein-coupling defect | Sbai et al. (unpublished) | |
| – | 420C > G | Y140X | Third transmembrane domain | NMD or protein truncation | Abreu et al. (2010) |
| 2 | 491G > A | R164Q | Second intracellular loop | Mild G protein-coupling defect | Dodé et al. (2006), Cole et al. (2008), Monnier et al. (2009) |
| – | 518T > G | L173R | Fourth transmembrane domain | Cell surface-targeting defect | Dodé et al. (2006), Abreu et al. (2010), Cole et al. (2008), Monnier et al. (2009) |
| – | 533G > C | W178S | – | Cell surface-targeting defect | Dodé et al. (2006), Cole et al. (2008), Monnier et al. (2009) |
| – | 563C > T | S188L | – | Strong G protein-coupling defect | Cole et al. (2008), Sbai et al. (unpublished) |
| – | 604A > G | S202G | Second extracellular loop | ? | Chan et al. (2009) |
| – | 629A > G | Q210R | – | Ligand-binding defect | Dodé et al. (2006), Monnier et al. (2009) |
| 701G > A | G234D | Fifth transmembrane domain | Cell surface-targeting defect | Sbai et al. (unpublished) | |
| – | 743G > A | R248Q | Third intracellular loop | None? | Cole et al. (2008) |
| – | 752G > T | W251L | – | Strong G protein-coupling defect? | Sarfati et al. (2010), Sbai et al. (unpublished) |
| – | 802C > T | R268C | – | G protein-coupling defect? | Dodé et al. (2006), Abreu et al. (2010), Monnier et al. (2009), Sarfati et al. (2010) |
| – | T820 > A | V274D | Sixth transmembrane domain | Strong G protein-coupling defect | Sinisi et al. (2008), Sbai et al. (unpublished) |
| – | 868C > T | P290S | – | Cell surface-targeting defect | Dodé et al. (2006), Monnier et al. (2009) |
| – | 969G > A | M323I | Seventh transmembrane domain | None? | Dodé et al. (2006), Monnier et al. (2009) |
| – | 989del | Frameshift | – | NMD or protein truncation | Sarfati et al. (2010) |
| – | 991G > A | V331M | – | Mild G protein-coupling defect | Dodé et al. (2006), Cole et al. (2008), Monnier et al. (2009), Sarfati et al. (2010) |
| – | 1069C > T | R357W | C-terminal region | None? | Cole et al. (2008), Sbai et al. (unpublished) |
| PROK2 | |||||
| 1 | −4C > A | Translation initiation site | Reduced protein synthesis? | Dodé et al. (2006) | |
| – | 70G > C | A24P | Signal peptide | ? | Cole et al. (2008) |
| – | 94G > C | G32R | AVITGA motif | Strongly impaired activity? | Dodé et al. (2006) |
| 2 | 101 G > A | C34Y | Cysteine-rich region | Strongly impaired activity | Cole et al. (2008) |
| – | 137G > A | C46Y | Cysteine-rich region | ? | Dodé et al. (unpublished) |
| – | 150C > G | I50M | – | None? | Cole et al. (2008) |
| – | 161G > A | S54N | – | ? | Sarfati et al. (2010) |
| – | 163del | Frameshift | – | NMD or protein truncation | Pitteloud et al. (2007), Leroy et al. (2008) |
| – | 217C > T | R73C | – | Strongly impaired activity | Dodé et al. (2006), Leroy et al. (2008), Cole et al. (2008) |
| 4 | 297_298insT | Frameshift | – | NMD or protein truncation | Dodé et al. (2006), Abreu et al. (2010) |
| 301C > T | R101W | – | ? | Dodé et al. (unpublished) | |
| – | 302G > A | R101Q | – | ? | Dodé et al. (unpublished) |
| – | 310C > T | H104Y | – | ? | Sarfati et al. (2010) |
Mutations reported in PROKR2 and PROK2 are mainly missense mutations. In most patients, the mutations have been found in heterozygous state. The R85C, R85H, R164Q, L173R, and P290S PROKR2 mutations, as well as R73C, c.163del, and c.297_298insT PROK2 mutations have, however, been found both in heterozygous and homozygous (or compound heterozygous) states, which suggests that patients heterozygous for PROKR2 or PROK2 mutations carry additional mutations, presumably in other, as yet unidentified Kallmann syndrome genes in most cases. Notably, two such patients have the L173R mutation in PROKR2 together with S396L or R423X mutations in KAL1 (Dodé et al., 2006; Sarfati et al., 2010), another patient has the V115M mutation in PROKR2 together with the A24P mutation in PROK2 (Cole et al., 2008), and still another patient has the R85L mutation in PROKR2 together with a A604T mutation in FGFR1 (Sarfati et al., 2010). In addition, the patient who has the S202G mutation in PROKR2 also has I239T and R31C monoallelic mutations in FGFR1 and GNRH1, respectively (Chan et al., 2009). Finally, two patients who carry R268C and V331M mutations in PROKR2 also carry A189T and R240Q monoallelic mutations in KISS1R and GNRHR, respectively (Sarfati et al., 2010). Abbreviation: NMD, nonsense-mediated mRNA decay.
?, not known.