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Proximal Dominant Hereditary Motor and Sensory Neuropathy Association with Mutation in the TRK-Fused Gene

Proximal Dominant Hereditary Motor and Sensory Neuropathy Association with Mutation in the TRK-Fused Gene

Supplementary Online Content

Lee S-S, Lee HJ, Park J-M, et al. Proximal dominant hereditary motor and sensory neuropathy association with mutation in the TRK-fused gene. JAMA Neurol. Published online March 18, 2013. doi:10.1001/jamaneurol.2013.1250.

eTable 1. Sample list in FC457 family eTable 2. Microsatellites used for chromosomal mapping of 3q1-q2 and their primers for PCR eTable 3. Nonsynonymous variants which are present in three affected individuals (III-23, -27, -29), but not in an unaffected individual (III-25) eTable 4. Nonsynonymous variants found in CMT genes from the proband (III-27) exome data eFigure 1. Diagram of chromosome 3 mapping region for HMSN-P eFigure 2. TFG expression in the distal sural nerve eReferences.

This supplementary material has been provided by the authors to give readers additional information about their work.

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eTable 1. Sample list in FC457 family

Samples Sex/age Affected Onset DNA testingb CMT Statusa age(year) phenotype (A/U) II-6 F/89 U - No, L - II-16 M/72 U - No - III-3 F/69 U - No - III-4 F/67 U - No - III-7 F/65 U - No, L - III-12 F/68 U - No, L - III-16 F/52 U - No, L - III-18 F/62 U - No, L - III-23 M/56 A 45 Yes, L, E HMSN-P III-25 M/55 U - No, L, E - III-27 M/51 A 48 Yes, L, E HMSN-P III-28 F/48 U - No, L - III-29 F/48 A 46 Yes, L, E HMSN-P III-30 M/50 U - No, L - III-32 M/59 U - No - III-34 F/58 U - No - IV-1 F/50 U - No - IV-4 M/45 U - No - IV-8 F/34 U - No - IV-9 F/32 C/U - No - IV-10 F/33 C/U - No - IV-11 M/31 A 29 Yes, L HMSN-P IV-12 F/28 C/U - Yes - IV-13 M/27 U - No - IV-17 M/23 C/U - Yes, L - IV-18 F/20 U - No, L - IV-19 M/27 A 27 Yes, L HMSN-P IV-20 M/21 U - No, L -

aA: affected, U: unaffected, C/U: clinically unaffected. bSamples with TFG (P285L) mutation (Yes) or without mutation (No), linkage analyzed for 3q (L), and exome studied (E).

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eTable 2. Microsatellites used for chromosomal mapping of 3q1-q2 and their primers for PCR

Marker Position (bp)a Repeat Forward primer Reverse primer D3S0490i 81,376,314-81,376,660 GT TTGTATCAAAGCATCTTGTGTA GCCTTAATATTTGTTCTCCAAC D3S1496i 90,151,487-90,151,710 GT TGAGGTTGGGAGATTCATTAC TGTCTAGCTGAGTATTTGCACAC D3S1488i 97,819,999-97,820,344 ATCT CTTAGGCTCCTTAATTCCAAAC TGGATAATTAGGTCAAGAGCTATC MK447017 99,591,050-99,591,260 GT CATCAGAACAGCAAACATTCA TGGATCAGATGACCTCCATT D3S1592i 100,330,045-100,330,474 TTCC CCTCATTTAAAGGACATACTTCAC AGCTGGTATGCCTCTATTGTTAG D3S3652 102,003,622-102,003,945 CA GAAAAATAGTCTCCAGTCAAGTAGC ATGCCCATCAATCAATGAGT D3S1083i 105,165,297-105,165,656 CA CAGTTGCACTATGGAGTATAAATC GATCAACTCCTGTAGATTCTACAG D3S0532i 105,834,654-105,835,054 GT GTAAACAATCTTGTGCATCAAG AGTTAAGTACTGTTACTTGGCCTC D3S1271 100,734,730-100,734,966 CA TGATTGGAGGTGGTAGAGGT AGCTATCATGTAGAAAAGCAGCA D3S2495 108,136,425-108,136,792 CA ATCTGTAAGNTCTGCTTTGTGAAT AAATATTGTATGCGATGTGATTTA GATA146G09 111,062,838-111,063,230 CTAT AGTCATTGTCAGGCATTGGT ATATGACCTTGGGCAACAAA D3S1278 115,124,154-115,124,458 CA GGACACATGCTCCTGGAA TGCACTACAGGGCAGTTG D3S1303 118,158,274-118,158,597 CA CAGACAATGGCTTCCAAAAGTA CAAACTTAGGGTTGTTCCTCAC D3S3576 122,245,333-122,245,473 CA GATCTAGTTGGCAAGGCGT TTGGACTCGAGCAATCC D3S1587 130,798,818-130,799,234 CA TACAGTTCTATAAGGGCAGCC AGGGAGACAGAGTGATGGATT D3S1309 140,726,314-140,726,687 CA CTTTGGGGAATCATTAGTCTGT ATGAGAATTGTCATGGTGC D3S3531 154,213,339-154,213,674 CA AAGAGCCTAAATTAGGAAAATAAAA AAACAAAGCAAGACTCCATC D3S3580 159,618,270-159,618,613 CA GCCATTGCAGAGAAGTTTGA TGGGGCTACAGTTACAAGGG D3S1258 165,925,381-165,925,702 CA CGAAGAGGCACTTGCAC TGGCTGAATAAAATGATAACAC

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eTable 3. Nonsynonymous variants which are present in three affected individuals (III-23, -27, -29), but not in an unaffected individual (III-25)

Positiona Nucleotide Amino acid Other Gene RefSeqb (Chr: position) changec change descriptiond 1: 166944483 ILDR2 NM_199351 c.23G>C W8S Pol 2: 55187450 EML6 NM_001039753 c.4948C>T R1650C Priv 2: 99008386 CNGA3 NM_001298 c.626C>T S209L Pol 2: 113764226 IL36A NM_014440 c.176G>C R59T Pol 2: 130877775 POTEF NM_001099771 c.314G>T C105F Pol 2: 133543219 NCKAP5 NM_207363 c.1165A>G N389D Pol 2: 141946101 LRP1B NM_018557 c.902A>G D301G Priv 2: 179634421 TTN NM_003319 c.8749A>C T2917P Pol 3: 14724702 C3orf20 NM_001184958 c.116C>T S39L Pol 3: 100364791 GPR128 NM_032787 c.949T>C Y317H Priv 3: 100467026 TFG NM_006070 c.854C>T P285L Causative 4: 57316850 PAICS NM_001079524 c.753G>A W251X Priv 10: 30728081 MAP3K8 NM_005204 c.214T>C W72R Pol 15: 42453967 VPS39 NM_015289 c.2465A>G Q822R Pol 15: 45657007 GATM NM_001482 c.1030A>G I344V Priv 15: 52242143 LEO1 NM_138792 c.1660C>T R554C Priv 16: 14234516 MKL2 NM_014048 c.53A>T H18L Priv 16: 19883478 GPRC5B NM_016235 c.690G>T K230N Priv 16: 24953358 ARHGAP17 NM_001006634 c.1440G>C K480N Priv 16: 30980685 SETD1A NM_014712 c.2830C>T R944W Priv 16: 31102595 VKORC1 NM_206824 c.242G>C C81S Pol 12: 57910273 MARS NM_004990 c.2612C>T A871V Pol

aReference nucleotide position: UCSC assembly hg19. bGenBank registration number of reference sequence. ccDNA numbering was achieved with +1 corresponding to the A of the ATG initiation codon. dPol: polymorphic variant (identified in controls), Priv: private variants which were not cosegregated with affected individuals, but were not found in 200 or more controls.

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eTable 4. Nonsynonymous variants found in CMT genes from the proband (III-27) exome data

Read Mutant Nucleotide Amino acid dbSNP135/ Gene Chr:positiona RefSeqb Descriptione depth allele No changec change 1000Genomed KIF1B 1:10397567 NM_015074.3 40 24 c.3260A>G Y1087C rs2297881/1000g Het, Pol FIG4 6:110064928 NM_014845.4 95 54 c.1090A>T M364L rs2295837/1000g Het, Pol FIG4 6:110107517 NM_014845.4 43 43 c.1961T>C V654A rs9885672/1000g Hom, Pol GARS 7:30634661 NM_002047.2 13 13 c.124C>G P42A rs1049402/1000g Hom, Pol IKBKAP 9:111641825 NM_003640.3 66 30 c.3473C>T P1158L rs1538660/1000g Het, Pol IKBKAP 9:111651620 NM_003640.3 29 11 c.3214T>A C1072S rs3204145/1000g Het, Pol IKBKAP 9:111659483 NM_003640.3 149 81 c.2446A>C I816L rs2230793/1000g Het, Pol LRSAM1 9:130242166 NM_138361.5 44 24 c.952A>G N318D rs1539567/1000g Het, Pol SETX 9:135139826 NM_015046.5 39 16 c.7834A>G S2612G rs3739927/1000g Het, Pol SETX 9:135139901 NM_015046.5 65 65 c.7759A>G I2587V rs1056899/1000g Hom, Pol WNK1 12:994487 NM_014823.2 70 70 c.3776G>C C1259S rs7955371/1000g Hom, Pol WNK1 12:998365 NM_014823.2 61 30 c.4683G>T M1561I rs12828016/1000g Het, Pol SEPT9 17:75494705 NM_006640.4 32 32 c.1672A>G M558V rs2627223/1000g Hom, Pol DNM2 19:10935797 NM_004945.3 115 62 c.1946T>G V649G /1000g Het, Pol PRX 19:40900865 NM_181882.2 59 59 c.3394G>A G1132R rs268674/1000g Hom, Pol

aReference nucleotide position: UCSC assembly hg19. bGenBank registration number of reference sequence. ccDNA numbering was achieved with +1 corresponding to the A of the ATG initiation codon. dc.1946T>C (V649G) in DNM2 was reported in 1000genome, but not in dbSNP135. eHet: heterozygous, Hom: homozygous, Pol: polymorphic.

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eFigure 1. Diagram of chromosome 3 mapping region for HMSN-P. Markers with bold letters (from D3S3652 to D3S3531) indicate cosegregating markers in this study. The linkage regions, reported by several previous studies, are indicated by vertical double oriented arrows.1-3 The GPR128 and TFG locate between D3S1592i and D3S3652 within the linkage maps by Maeda et al,1 and Takashima et al,2 as well as map by this study, but deviate slightly from the narrowed map by Takashima et al.3

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eFigure 2: TFG expression in the distal sural nerve. Transcriptome was sequenced in three samples: a patient (III-29, F/48) and two controls (F/37, and F/38). The cDNA library was prepared using the TruSeq RNA library kit, and paired-end sequencing was performed using the HiSeq2000 Genome Analyzer (Illumina). The expression levels were indicated by fragments per kilobase per million sequenced reads (FPKM) after normalizing beta-actin gene expression.

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eReferences

1. Maeda K, Kaji R, Yasuno K, et al. Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity. J Hum Genet. 2007;52(11):907-914.

2. Takashima H, Nakagawa M, Nakahara K, et al. A new type of hereditary motor and sensory neuropathy linked to chromosome 3. Ann Neurol. 1997;41(6):771-780.

3. Takashima H, Nakagawa M, Suehara M, et al. Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1. Neuromuscul Disord. 1999;9(6-7):368- 371.

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