Supplementary Table 2. WRN Mutations in Werner Syndrome Patients

Supplementary Table 2. WRN mutations in Werner syndrome patients

Nucleotide and amino acid notations are based on the reference sequences, GenBank accession numbers, NM_000553.4, NP_000544.2 and NC_000008.10 (NCBI Build 36.1). The descriptions of the mutations follow the nomenclature guideline of the Human Genome Variation Society (http://www.hgvs.org/mutnomen/). Abbreviations: 1 mut, only one mutation was identified although clinical presentations and/or Western analysis indicated that both alleles are mutated; cau, Caucasian; comp, compound heterozygous; del, deletion; Fb, fibroblasts; Fb*, fibroblasts immortalized with hTERT are also available; fs, frame shift; HRDC, helicase, RNaseD, C-terminal conserved region; ins, insertion; LCL, lymphoblastoid cell line; mut, mutation; hom, homozygous; sub, substitution; transvn, transversion; transtn, transition; splice junc, splice junction; RQC, RecQ helicase conserved region; X, stop codon.

Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments Sub:transvn 1 WU1010 Comp German(cau) DNA Nonsense c.171C>G p.Y57X 3 (Huang et al. 2006) TAC>TAG Splice junc (Huang et al. 2006) c.356-2A>C 2 AB10010 Comp French (cau) LCL Sub:transvn p.V119fs IVS4 exonuclease (Uhrhammer et al. 2006) r.356_366del11 New splice site This study

3 STU1010 Hom German(cau) DNA Sub:transvn c.375A>T p.K125N 5 exonuclease (Huang et al. 2006)

4 STU1010 Hom German(cau) DNA Sub:transvn c.403A>G p.K135E 5 exonuclease (Huang et al. 2006)

Deletion c.474delT p.F158fs 5 exonuclease (Uhrhammer et al. 2006) 5

6 JV90700 Hom French(cau) LCL Ins/Deletion c.487_489delGATinsC p.D163fs 5 exonuclease (Huang et al. 2006)

7 Japanese Deletion c.502_503delAA p.K168fs 5 exonuclease (Matsumoto et al. 1997)

Splice junc c.655-1G>A 8 CP70530 Hom French(cau) LCL Sub:transvn p.A219fs IVS6 exonuclease (Huang et al. 2006) r.655_724del70 Skip exon 7 Splice junc c.724+1G>T 9 TOR1010 Comp Canadian (cau) LCL Sub: transvn p.A219fs IVS7 exonuclease This study r.655_724del70 Skip exon 7 c.867_874del 10 RO1010 Hom Italian (cau) LCL Deletion p.E290fs 9 (Huang et al. 2006) AGAAAATC

1 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments AED80300 Comp Celtic(cau) DNA AG00780 Hom Caucasian Fb AG4103 Hom Caucasian Fb AU1010 Hom Austrian(cau) LCL, Fb* BERI1010 Comp German(cau) DNA BET5010 Comp USA(cau) LCL 11 BO1010 Comp Dutch LCL CDR60010 Comp USA(cau) LCL CH1010 Comp German(cau) DNA CLF05010 Comp French(cau) LCL CP2650 Hom French(cau) DNA CP3 Comp, 1mut French(cau) DNA CP87210 Comp French(cau) LCL DJG Comp German(cau) LCL DU1010 Comp Dutch (cau) DNA (Oshima et al. 1996) DR1010 Comp German(cau) DNA EKL Hom SwissGerman LCL HAW1010 Comp Japanese LCL Sub: transtn HEI1010 Comp German(cau) LCL Nonsense c.1105C>T p.R369X 9 Most common among INU1010 Hom USA(cau) LCL CGA>TGA Caucasian WS. Second KO90375 Hom Japanese DNA most common among KUN9001 Comp Japanese LCL Japanese WS. LGS90610 Hom USA(cau) LCL NF Comp, 1mut French(cau) LCL OW90650 Hom Japanese LCL OW90660 Hom Japanese DNA PC70010 Comp USA(cau) DNA RI1010 Hom Puerto Rican(cau) LCL RI1030 Hom Puerto Rican(cau) LCL SW1010 Comp Swiss(cau) DNA

12 PC70010 Comp USA(cau) DNA Ins/Deletion c.1123_1124delGAinsC p.E375fs 9 (Huang et al. 2006)

AB10010 Comp French(cau) LCL 13 AU40025 Comp Austrian LCL AU40030 Comp Austrian LCL Deletion c.1165delA p.R389fs 9 (Oshima et al. 1996) CLF05010 Comp French(cau) LCL FES Comp, 1mut German LCL LU1010 Comp German DNA

14 CL11010 Comp, 1mut French DNA Deletion c.1250_1253delTTGC p.A418fs 9 (Huang et al. 2006)

Insertion c.1278_1279insATCT p.P427fs 10 (Oshima et al. 1996) 2 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments 15 MIM37100 Hom Brazil (cau) LCL

16 MA1010 Hom Spain (cau) LCL MA1020 Hom Spain (cau) LCL Deletion c.1316_1319delAGAG p.E439fs 10 This study MA1030 Hom Spain (cau) LCL MA1040 Hom Spain (cau) LCL

Sub: transvn 17 Japanese Nonsense c.1389T>A p.Y463X 11 (Matsumoto et al. 1997) TAT>TAA Sub:transvn 18 HE90750 Hom French (cau) LCL Nonsense c.1462G>T p.E488X 12 (Huang et al. 2006) GAA>TAA Sub: transvn 19 BER1010 Comp German DNA Nonsense c.1486A>T p.K496X 12 (Huang et al. 2006) AAA>TAA

201 WB8010 Hom German(cau) Fb Deletion c.1486_1489delAAAA p.K496fs 12 (Huang et al. 2006)

Sub: transtn 21 BO1010 Comp Dutch LCL c.1586G>A p.W529X 13 This study TGG>TAG

c.1674_1677delTTCA 22 NZ1010 Comp New Zealand LCL Deletion p.H558fs 14 helicase (Huang et al. 2006) (cau)

23 HN2010 Comp Gernan DNA Sub: transtn c.1720G>A p.G574R 14 helicase This study

24 CDR60010 Comp USA (cau) LCL Deletion c.1801_1802delCT p.L601fs 15 helicase (Huang et al. 2006)

Splice junc c.1829+2T>G 25 VTC1010 Homo Portugal (cau) LCL Sub: transvn p.G574fs IVS15 helicase This study r.1721_1829del109 Exon 15 skip Sub: transtn 26 Missense c.1909C>T p.R637W 17 helicase (Uhrhammer et al. 2006) CGG>TGG Splice junc c.1982-1G>A 27 HN2010 Comp German DNA Sub: transtn p.I662fs IVS17 helicase This study r.1982_2088del107 Exon 18 skip

28 Deletion c.2003delA p.D668fs 18 helicase (Uhrhammer et al. 2006)

3 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments

29 TOR1010 Comp Canadian (cau) LCL Deletion c.2055delG p.K686fs 18 helicase This study

LRV80000 Hom Sardinia(cau) DNA Sub: transtn c.2089-3024A>G (Oshima et al. 1996) 30 LRV80001 Hom Sardinia(cau) DNA p.V697fs 18-19 helicase New exon r.2088_2089ins106 (Masala et al. 2007) SEP9000 Hom Sardinia(cau) LCL

CL31010 Comp French (cau) LCL 31 DR1010 Comp German DNA Deletion c.2103_2104delAC p.L702fs 19 helicase (Muller et al. 2005) LU1010 Comp German(cau) DNA

32 MO1010 Hom Moroccan LCL NI1010 Hom Moroccan DNA Insertion c.2179dupT p.C727fs 19 helicase (Huang et al. 2006) NI1020 Hom Moroccan

AM5010 Hom French (cau) LCL, Fb* Sub: transtn 33 GE1010 Hom Italian DNA Nonsense c.2194C>T p.R732X 19 helicase (Huang et al. 2006) SN1010 Hom Italian (cau) LCL CGA>TGA SN1020 Hom Italian (cau) LCL

Sub: transtn 34 DU1010 Comp Dutch(cau) DNA Nonsense c.2221C>T p.R741X 19 helicase This study CGA>TGA Sub: transtn 35 AG03141 Hom USA(cau) Fb Nonsense c.2242C>T p.Q748X 19 helicase (Choi et al. 2001) CGA>TGA Splice junc 36 MSA90025 Hom Italian LCL c.2448+1G>T Sub: transvn p.S759fs IVS20 helicase (Yu et al. 1997) WKH Hom Japanese LCL r.2274_2448del175 Skip exon 20

This study Skip exon 20 r.2274_2448del175 p.S759fs 20 helicase 37 SI1010 Comp USA(cau) LCL ?Leaky mutation Sub: transtn 38 Nonsense c.2283G>A p.W761X 20 helicase (Uhrhammer et al. 2006) TGG>TGA Sub: transtn 39 AS1010 Hom USA(cau) DNA Nonsense c.2581C>T p.Q861X 21 helicase (Huang et al. 2006) CAA>TAA Sub: transtn c.2665C>T p.R889X 22 RQC (Oshima et al. 1996) CP87210 Comp French(cau) LCL Nonsense 4 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments CTA Hom Africa/India LCL 40 NC8010 Hom USA(cau, Jew) LCL SI1010 Comp USA(cau) LCL CGA>TGA SUG17802 Comp USA(cau) LCL

41 WV Comp, 1mut Unknown SV40 Fb Deletion c.2773delG p.A925fs 23 RQC (Bennett et al. 1997)

Splice junc c.2826-1G>C 42 HEI1010 Comp German (cau) LCL Sub: transvn p.L943fs IVS23 RQC (Huang et al. 2006) r.2826_2967del142 Skip Exon 24 Sub: transvn 43 VEL1010 Hom India LCL Nosense c.2855C>A p.S952X 24 RQC This study TCA>TAA Sub: transtn 44 MY1010 Hom Korean LCL Nonsense c. 2884C>T p.Q962X 24 RQC (Huang et al. 2006) CAA>TAA Sub: transtn 45 SW1010 Comp Swisss(cau) DNA Nonsense c. 2959C>T p.R987X 24 RQC (Huang et al. 2006) CGA>TGA Splice junc c.2967+1G>A 46 USC1010 Hom Afgani LCL Sub: transtn p.L943fs IVS24 RQC This study r. 2826_2967del142 Exon 24 skip

47 CWW91001 Comp USA(cau) LCL RQC NZ1010 Comp New Zealand(cau) LCL Deletion c.3030_3033delAACA p.T1011fs 25 (Moser et al. 1999) JMP1010 Hom USA(cau) DNA

CWW91001 Comp USA(cau) LCL 48 TA1010 Hom Taiwanese DNA Deletion c.3037_3038delAG p.S1013fs 25 RQC (Huang et al. 2006) TA1020 Hom Taiwanese DNA VI1010 1 mut Austria(cau) LCL

49 BET5010 Comp Puerto Rican LCL Insertion c.3130dupA p.T1044fs 25 RQC (Huang et al. 2006)

Splice junc c.3139-1G>C p.G1047fs IVS25 (Yu et al. 1996) AO1010 Hom Japanese Fb Sub: transvn r.3139_3233del95 FJ Hom Japanese LCL Skip exon 26 Most common mutation FUW Hom Japanese DNA in Japanese WS 50 HA Hom Japanese LCL HAW1010 Comp Japanese LCL HW90600 Hom Japanese DNA HW90605 Hom Japanese LCL 5 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments IU Hom Japanese LCL JO1 Hom Japanese LCL JO2 Hom Japanese LCL KAKU Hom Japanese DNA KY Hom Japanese LCL MCI7326 Hom Japanese Fb* MCI7882 Hom Japanese Fb MIE2 Hom Japanese LCL MIK1010 Hom Japanese LCL SK Hom Japanese LCL ST Hom Japanese LCL TH Hom Japanese LCL TK Hom Japanese LCL TO Hom Japanese LCL ZM90625 Hom Japanese LCL ZM90630 Hom Japanese LCL

CP60010 Hom French (cau) LCL Splice junc c.3233+1G>C 51 CP60020 Hom French (cau) LCL Sub:transvn p.G1047fs VS26 (Huang et al. 2006) r.3139_3233del95 CP60040 Hom French (cau) LCL Skip exon 26

Sub: transtn c.3234-160A>G 52 CO1010 Hom Turk LCL p.S1078fs IVS26 This study New exon r.3233_3234ins69

53 Deletio c.3244_3245delGT p.V1082fs 27 (Uhrhammer et al. 2006)

54 SP1010 Hom Spain (cau) LCL Sub:transvn c.3319G>T p.E1107X 28 This study

Splice junc c.3383+1G>T 55 KUN9001 Comp Japanese LCL Sub:transvn p.S1104fs IVS28 (Oshima et al. 1996)] r.3310_3383del74 Skip exon 28

56 IB90550 Hom Japanese LCL Deletion c.3446delA p.E1149fs 29 (Oshima et al. 1996)

Splice junc c.3460-7T>A 57 Japanese Sub: transvn p.I1154fs IVS29 (Matsumoto et al. 1997) r.3459_3460insTTCAG New splice site

58 HU1010 Hom Turk DNA Splice Junc IS1010 Hom Turk LCL Sub:transtn c.3460-2A>G p.I1154fs IVS29 HRDC (Huang et al. 2006) BUL1010 Hom Turk LCL Skip exon 30 Sub:transtn c.3493C>T p.Q1165X 30 HRDC (Yu et al. 1996) 6 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments BLS60010 Hom French LCL 59 OS1010 Hom Turk DNA OS1020 Hom Turk DNA Nonsense SY90575 Hom Japanese LCL CAG>TAG TU90010 Hom Turk LCL

Sub:transvn 60 Nonsense c.3496A>T p.K1166X 30 HRDC (Uhrhammer et al. 2006) AAA>TAA

AED80300 Comp Celtic(cau) DNA Splice junc c.3572+2T>A 61 AU40025 Comp Austrian(cau) LCL Sub:transvn p.I1154fs IVS30 HRDC (Oshima et al. 1996) r.3460_3572del113 AU40030 Comp Austrian(cau) LCL Skip exon 30

62 UT1010 Comp Dutch DNA Deletion c.3590delA pN1197fs 31 HRDC (Huang et al. 2006) ER1010 Hom Dutch DNA

CL31010 Comp French LCL SYR10006 Hom Syrian LCL (Oshima et al. 1996; Yu 63 SYR10007 Hom Syrian LCL Deletion c.3690_3693delACAG p.D1231fs 32 et al. 1996) SYR10008 Hom Syrian LCL SYR10011 Hom Syrian LCL LCL Sub: transvn 64 Nonsense c.3789C>G p.Y1263X 32 (Uhrhammer et al. 2006) TAC>TAG

GAR90675 Hom Mexican(cau) DNA 65 HH80350 Hom Japanese DNA Sub: transtn HM90075 Hom Japanese LCL Nonsense c.3913C>T p.R1305X 33 (Yu et al. 1996) MH90925 Hom Japanese LCL CGA>TGA NN90150 Hom Japanese DNA

66 Japanese Insertion c.3915dupA p.A1306fs 33 (Goto et al. 1997)

Sub: transtn 67 CH1010 Comp German (cau) DNA Nonsense c.3961C>T p.R1321X 33 This study CGA>TGA This study 68 UT1010 Comp Dutch DNA Sub: transvn c.4049T>G p.M1350R 34 Predicted damaging

7 Mutation Country/ Materials Nucleotide Protein Domain Reference/ No Registry # Mutation Type Exon Status Ethnicity Available Notation Notation Location Comments

chr8:g.(31,018,011_31,019,559)_ Exonuclease This study 69 CP97510 Hom* French LCL Duplication* 2-18 (31,079,038_31,082,235)dup* Helicase * See text for detail

DJG Comp German(cau) LCL (Oshima et al. 1996) 70 SA2010 Hom USA(cau) LCL Large deletion chr8:g.31,078,664_31,105,734del 19-23 helicase (Yu et al. 1997) SUG17802 Comp USA(cau) LCL

chr8:g.31,089,233_31,642,239del Helicase, 71 WU1010 Comp German(cau) DNA Large deletion 20-35 This study ins32 RQC,HDRC