Table 3. Missense point mutations in SGSH and their expected effect based on the atomic structure of SGSH.
Abbreviations: NR, not reported; Interm., intermediate; sc, side chain, H bond, hydrogen bond; NASA, normalized accessible surface area per atom per residue (as a percentage of the maximal value for any internal residue in SGSH).
| Protein | Codon | Phenotype | NASA | Type | Effect of mutation on structure | Reference |
|---|---|---|---|---|---|---|
| M1V | 1A>G | NR | Signal peptide | Part of signal peptide | Pollard et al. (2013 ▶) | |
| L12Q | 35T>A | Late | Signal peptide | Part of signal peptide | Valstar et al. (2010 ▶) | |
| A30P | 88G>C | NR | 0 | Buried | Steric clash close to Ca2+-binding site; loss of H bond to Thr271 | Pollard et al. (2013 ▶) |
| D32G | 95A>G | Early | 1 | Metal binding | Disruption of Ca2+ binding | Beesley et al. (2000 ▶) |
| D32E | 96C>A/G | Late | 1 | Metal binding | Altered Ca2+ binding | Meyer et al. (2008 ▶) |
| G33R | 97G>A | NR | 4 | Buried | Introduces bulky sc next to Ca2+-binding Asp32 | Pollard et al. (2013 ▶) |
| Y40N | 118T>A | Interm. | 13 | Surface | Loss of H bonding to Leu294 and Phe60, and of -stacking interactions; next to glycosylation site | Di Natale et al. (1998 ▶) |
| N42K | 126C>A | Early | 6 | Surface | Loss of H bonding to Ala44, Ile45 and Tyr240; steric clash | Lee-Chen et al. (2002 ▶) |
| A44T | 130G>A | Early | 31 | Surface | Steric clash at surface site | Di Natale et al. (1998 ▶), Esposito et al. (2000 ▶) |
| S66W | 197C>G | Early | 2 | Buried | Introduction of bulky sc in buried position in loop close to active site | Blanch et al. (1997 ▶), Weber et al. (1997 ▶), Di Natale et al. (1998 ▶), Montfort et al. (1998 ▶), Beesley et al. (2000 ▶), Chabs et al. (2001 ▶), Piotrowska et al. (2009 ▶), Valstar et al. (2010 ▶), Muschol et al. (2011 ▶), Pollard et al. (2013 ▶) |
| R74C | 220C>T | Early | 0 | Buried | Disruption of ion pairs/H bonds with Ca2+-binding Asp31, FGly70 and Asp273; possible interference with disulfide-bridge formation | Bunge et al. (1997 ▶), Weber et al. (1997 ▶), Di Natale et al. (1998 ▶), Beesley et al. (2000 ▶), Esposito et al. (2000 ▶), Emre et al. (2002 ▶), Muschol et al. (2004 ▶, 2011 ▶), Meyer et al. (2008 ▶), Piotrowska et al. (2009 ▶), Valstar et al. (2010 ▶), Pollard et al. (2013 ▶) |
| R74H | 221G>A | Early | 0 | Buried | Disruption of ion pairs/H bonds with Ca2+-binding Asp31, FGly70 and Asp273 | Bunge et al. (1997 ▶), Chabs et al. (2001 ▶) |
| T79P | 235A>C | Early | 0 | Buried | Disruption of H bonding to Ala75, Ser76 and Leu81 | Weber et al. (1997 ▶), Beesley et al. (2000 ▶), Pollard et al. (2013 ▶) |
| H84Y | 250C>T | Early | 1 | Buried | Loss of H bond to Ser364 and Thr475; steric clash in buried position | Beesley et al. (2000 ▶) |
| Q85R | 254A>G | Early | 3 | Buried | Steric clash | Montfort et al. (1998 ▶), Chabs et al. (2001 ▶) |
| M88T | 263T>C | NR | 0 | Buried | Destabilizes van der Waals interactions in buried position; steric clash | Fiorentino et al. (2006 ▶) |
| G90R | 268G>A | Early | 0 | Buried | Gain of bulky sc in buried position; change of / angles | Bunge et al. (1997 ▶), Piotrowska et al. (2009 ▶) |
| S106R | 318C>A | Late | 0 | Buried | Loss of H bond to Leu109, Val131; clash possibly accommodated within longer, partially surface-exposed loop | Muschol et al. (2004 ▶) |
| T118P | 352A>C | NR | 0 | Buried | Loss of H bonds to Asp135; destabilizes -sheet | Zhang Huiping (2008 ▶) |
| G122R | 364G>A | Interm. | 1 | Buried | Bulky sc in buried position; Gly / angles | Bunge et al. (1997 ▶), Di Natale et al. (1998 ▶), Beesley et al. (2000 ▶), Valstar et al. (2010 ▶), Pollard et al. (2013 ▶) |
| P128L | 383C>T | Late | 22 | Surface | Favourably surface-exposed to minimize steric clash; in loop with FGly-binding His125 and Lys123 | Di Natale et al. (1998 ▶, 2003 ▶) |
| V131M | 391G>A | Early | 1 | Buried | Bulky sc in buried position; destabilizes loop with FGly-binding residues | Weber et al. (1997 ▶) |
| T139M | 416C>T | Early | 1 | Buried | Bulky sc in buried position; loss of H bond to Glu141 | Weber et al. (1997 ▶) |
| L146P | 437T>C | Early | 11 | Surface | Loss of H bond to Ser144; some clash at surface; destabilizes helix 5; close to glycosylation site (Asn151) | Di Natale et al. (1998 ▶) |
| R150W | 448C>T | Early | 1 | Buried | Introduction of bulky aromatic sc; loss of salt bridge with Asp179, H bonding to His181 | Beesley et al. (2000 ▶), Chabs et al. (2001 ▶) |
| R150Q | 449G>A | Early | 1 | Buried | Loss of ion pair with Asp179, H bonding to His181; next to glycosylated Asn151 | Bunge et al. (1997 ▶), Di Natale et al. (1998 ▶), Chabs et al. (2001 ▶), Valstar et al. (2010 ▶), Montfort et al. (1998 ▶) |
| L163P | 488T>C | Early | 8 | Buried | Disruption of hydrophobic interactions, H bond to Val159; clash; destabilizes helix 6 | Muschol et al. (2004 ▶) |
| D179N | 535G>A | Early | 1 | Buried | Loss of buried salt bridges with Arg150, Arg245 | Di Natale et al. (1998 ▶), Esposito et al. (2000 ▶) |
| P180L | 539C>T | Late | 0 | Buried | Some steric clash next to active site-residues Asp31 and His181 | Valstar et al. (2010 ▶) |
| R182C | 544C>T | Interm. | 4 | Buried | Loss of ion pair with Asp235, H bond to Pro277 close to active site; possible interference with disulfide-bridge formation | Di Natale et al. (1998 ▶), Valstar et al. (2010 ▶) |
| G191R | 571G>A | Early | 11 | Surface | Surface-exposed but steric clash with scs of Glu195 and Lys196; Gly / angles | Muschol et al. (2004 ▶), Valstar et al. (2010 ▶) |
| F193L | 579C>G | NR | 0 | Buried | Disrupts -stacking next to active-site loop (His181) | Bunge et al. (1997 ▶), Yogalingam Hopwood (2001 ▶) |
| R206P | 617G>C | Late | 73 | Surface | Suface-exposed; Arg206 has no backbone amide H bond to lose; close to glycosylated Asn151; change in / angles | Montfort et al. (1998 ▶), Esposito et al. (2000 ▶), Chabs et al. (2001 ▶), Gabrielli et al. (2005 ▶) |
| P227R | 680C>G | Early | 0 | Buried | Steric clash from bulky substitution disrupts packing in buried position | Di Natale et al. (1998 ▶), Esposito et al. (2000 ▶) |
| A234G | 701C>G | Early | 51 | Surface | Unclear; possibly destabilization of helix 7 | Weber et al. (1997 ▶) |
| D235N | 703G>A | Early | 1 | Buried | Loss of buried salt bridge with Arg182 and of H-bond acceptor | Beesley et al. (2000 ▶), Lee-Chen et al. (2002 ▶) |
| D235V | 704A>T | NR | 1 | Buried | Loss of buried salt bridge with Arg182 and of H bonds to Thr192 and Thr407 | Bunge et al. (1997 ▶) |
| T242T | 726C>T | NR | 0 | Buried | Unclear | Valstar et al. (2010 ▶) |
| R245H | 734G>A | Early | 0 | Buried | Loss of buried salt bridge with Asp179 and H bonds to Asp179 and Cys194; clash; packing of helix 7 | Blanch et al. (1997 ▶), Bunge et al. (1997 ▶), Weber et al. (1997 ▶, 1998 ▶), Beesley et al. (2000 ▶), Muschol et al. (2004 ▶, 2011 ▶), Meyer et al. (2008 ▶), Valstar et al. (2010 ▶), Pollard et al. (2013 ▶) |
| D247H | 739G>C | NR | 1 | Buried | Loss of H bonding to Leu50; clash | Valstar et al. (2010 ▶) |
| G251A | 752G>C | Late | 13 | Surface | Some clash with sc of His49 in surface-exposed site | Meyer et al. (2008 ▶), Muschol et al. (2011 ▶) |
| D273N | 817G>A | Early | 2 | Metal binding | Disrupts Ca2+ binding | Beesley et al. (2000 ▶) |
| Y286S | 857A>C | NR | 4 | Buried | Disruption of H bond to Glu437 and of -stacking interactions | Yogalingam Hopwood (2001 ▶) |
| P288S | 862C>T | Early | 5 | Buried | Possibly unsatisfied H bonding in sc of Ser in buried position | Emre et al. (2002 ▶) |
| P288L | 863C>T | NR | 5 | Buried | Steric clash | Pollard et al. (2013 ▶) |
| E292K | 874G>A | Late | 0 | Buried | Buried water might offer space to accommodate larger sc | Piotrowska et al. (2009 ▶) |
| P293T | 877C>A | NR | 3 | Buried | Steric clash; loss of Pro from three-residue loop | Di Natale et al. (2006 ▶) |
| P293S | 877C>T | Early | 3 | Buried | Unclear; loss of Pro from three-residue loop | Lee-Chen et al. (2002 ▶), Pollard et al. (2013 ▶) |
| S298P | 892T>C | Late | 1 | Buried | Loss of H bonds to Glu300, His301, but steric clash milder as buried water offers substitution space; favourable / angles (Ser297, Ser298) | Bunge et al. (1997 ▶), Beesley et al. (2000 ▶), Muschol et al. (2004 ▶, 2011 ▶), Meyer et al. (2008 ▶), Valstar et al. (2010 ▶), Pollard et al. (2013 ▶) |
| E300V | 899A>T | Early | 48 | Surface | Unclear; loss of surface salt bridge with Arg23; little steric clash | Bekri et al. (2005 ▶) |
| R304L | 911G>T | NR | 7 | Surface | Loss of surface salt bridge with Glu355 and of H bonds to Ala351 and Gln307; some steric clash | Di Natale et al. (2006 ▶), Pollard et al. (2013 ▶) |
| Q307P | 920A>C | Early | 38 | Surface | Loss of surface H bonds to Arg304; steric clash; destabilization of strand 8 | Bekri et al. (2005 ▶) |
| A311D | 932C>A | NR | 3 | Buried | Steric clash; buried charge; unsatisfied H bonding | Pollard et al. (2013 ▶) |
| D317H | 949G>C | NR | 4 | Buried | Steric clash; loss of H bonds to Ser314, Arg346 | Pollard et al. (2013 ▶) |
| T321A | 961A>G | NR | 0 | Buried | Loss of H bonds to Asp317, Leu348 and of van der Waals interactions | Bunge et al. (1997 ▶) |
| I322S | 965T>G | Late | 0 | Buried | Loss of van der Waals interactions, but I322S can H-bond to Leu318 | Beesley et al. (2000 ▶) |
| S347Y | 1040C>A | NR | 15 | Surface | Bulky aromatic in solvent-exposed position, but with minimal steric clash; loss of H bonds to Asp324, Leu349 | Valstar et al. (2010 ▶) |
| S347F | 1040C>T | Late | 15 | Surface | Bulky aromatic in solvent-exposed position, but with minimal steric clash; loss of H bonds to Asp324, Leu349 | Miyazaki et al. (2002 ▶) |
| A354P | 1060G>C | Early | 58 | Surface | Loss of H bond to Pro350; steric clash with Pro350; change in / angles | Montfort et al. (1998 ▶), Chabs et al. (2001 ▶) |
| E355K | 1063G>A | Early | 39 | Surface | Loss of surface salt bridge with Arg304 and of H bonds to Ser309, Glu310; charge switch | Beesley et al. (2000 ▶) |
| S364R | 1092C>G | NR | 1 | Buried | Loss of H bonds to Gln83 and His84; marked steric clash in buried position | Bunge et al. (1997 ▶) |
| E369K | 1105G>A | Early | 6 | Surface | Loss of H bond to Gln400; charge switch close to active site | Di Natale et al. (1998 ▶, 2003 ▶), Esposito et al. (2000 ▶), Valstar et al. (2010 ▶), Pollard et al. (2013 ▶) |
| Y374H | 1120T>C | Early | 2 | Buried | Unsatisfied H bonding; charge | Beesley et al. (2000 ▶) |
| R377C | 1129C>T | Early | 0 | Buried | Loss of buried salt bridge with Asp477 and of H bonds to Ser366, Met376; plausibly interference with disulfide-bridge formation | Di Natale et al. (1998 ▶), Lee-Chen et al. (2002 ▶) |
| R377H | 1130G>A | Early | 0 | Buried | Loss of buried salt bridge with Asp477 and of H bonds to Ser366, Met376 | Weber et al. (1997 ▶), Yogalingam Hopwood (2001 ▶), Bunge et al. (1997 ▶), Valstar et al. (2010 ▶) |
| R377L | 1130G>T | NR | 0 | Buried | Loss of buried salt bridge with Asp477 and of H bonds to Ser366, Met376 | Pollard et al. (2013 ▶) |
| Q380R | 1139A>G | Early | 2 | Buried | Gain of charge in buried position close to surface; steric clash may affect H bond to Arg382 | Weber et al. (1997 ▶), Valstar et al. (2010 ▶) |
| L386R | 1157T>G | Early | 0 | Buried | Introduction of charge and steric clash in buried position; disruption of hydrophobic interactions | Montfort et al. (1998 ▶), Chabs et al. (2001 ▶) |
| V387M | 1159G>A | NR | 2 | Buried | Bulky residue in buried position | Di Natale et al. (2006 ▶) |
| N389S | 1166A>G | NR | 0 | Buried | Loss of buried H bonds to Ala434, Glu437 | Pollard et al. (2013 ▶) |
| N389K | 1167C>A | NR | 0 | Buried | Loss of buried H bonds to Ala434, Glu437; steric clash | Bunge et al. (1997 ▶), Valstar et al. (2010 ▶) |
| L411R | 1232T>G | NR | 1 | Buried | Introduction of charge in buried position; steric clash; disruption of hydrophobic interactions | Valstar et al. (2010 ▶) |
| T415P | 1243A>C | NR | 34 | Surface | Loss of H bond to Leu411; steric clash with Leu411; kink in helix 11 close to glycosylation site | Pollard et al. (2013 ▶) |
| T421R | 1262C>G | Late | 16 | Surface | Loss of H bond to Trp423; solvent exposure accommodates bulky sc | Valstar et al. (2010 ▶) |
| R433W | 1297C>T | Early | 6 | Buried | Loss of buried H bonds to Asn284, Tyr430 and of charge; steric clash | Beesley et al. (2000 ▶), Yogalingam Hopwood (2001 ▶), Chabs et al. (2001 ▶), Muschol et al. (2004 ▶), Pollard et al. (2013 ▶) |
| R433Q | 1298G>A | Early | 6 | Buried | Loss of buried H bonds to Asn284, Tyr430 and of charge; destabilizes packing | Chabs et al. (2001 ▶), Di Natale et al. (2003 ▶), Valstar et al. (2010 ▶) |
| D444G | 1331A>G | Late | 13 | Surface | Loss of surface H bonds to Thr448, Gln449 | Miyazaki et al. (2002 ▶) |
| E447K | 1339G>A | Early | 8 | Surface | Switch of charge in partly buried location | Blanch et al. (1997 ▶), Chabs et al. (2001 ▶) |
| Q472H | 1416G>C | NR | 6 | Surface | Loss of H bond to Asp477 | Pollard et al. (2013 ▶) |
| V486F | 1456G>T | Late | 37 | Dimer interface | Disruption of dimer interface | Beesley et al. (2000 ▶) |