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A Splice Site Mutation in the Methyltransferase Gene FTSJ1 In 679 J Med Genet: first published as 10.1136/jmg.2004.019000 on 1 September 2004. Downloaded from SHORT REPORT A splice site mutation in the methyltransferase gene FTSJ1 in Xp11.23 is associated with non-syndromic mental retardation in a large Belgian family (MRX9) J Ramser, B Winnepenninckx, C Lenski, V Errijgers, M Platzer, C E Schwartz, A Meindl, R F Kooy ............................................................................................................................... J Med Genet 2004;41:679–683. doi: 10.1136/jmg.2004.019000 additional specific clinical or dysmorphic features. Carrier Mental retardation is the most frequent cause of serious women were unaffected. handicap in children and young adults. The underlying causes of this heterogeneous condition are both acquired and genetically based. A recently performed refinement of METHODS the linkage interval in a large Belgian family with mild to Subjects The MRX9 family is Caucasian and resides in Belgium as severe non-syndromic X linked mental retardation, classified described.78 The pedigree is shown in fig 1. DNA and RNA as MRX9, revealed a candidate region of 11.3 Mb between were extracted from blood samples and immortalised markers DXS228 and DXS1204 on the short arm of the X lymphoblastoid cell lines that were established from periph- chromosome. In order to identify the underlying disease gene eral lymphocytes using standard protocols. in the MRX9 family, we established a gene catalogue for the candidate region and performed comprehensive mutation Mutation analysis analysis by direct sequencing. A human homologue of the Mutation screening was carried out on genomic DNA and on bacterial 23S rRNA methyltransferase Fstj, the FTSJ1 gene, is cDNA. At the genomic level, the screening was performed by locatedwithinthisregionanddisplayedasequence exon sequencing with the adjacent intronic sequences using alteration in the conserved acceptor splice site of intron 3 BigDye kits (PerkinElmer, Heidelberg) with separation of the (IVS3-2A.G) in all tested patients and carrier females of this fragments on an ABI capillary sequencer (ABI 3100). For PCR family. In contrast, it was absent in all unaffected male family amplification the following primer pairs were used: af (exons members tested. The mutation results in skipping of exon 4 2–4): 59 -CTT CTG TGT GAG CTG TCA TG- 39, ar: 59 -GG CCT and introduces a premature stop codon in exon 5, probably TCA CCC AGG ATA TAC- 39, bf (exon 5): 59 -CCA GGT AAG leading to a severely truncated protein. Our finding indicates AGC ATG GCT G- 39, br: 59 -AGG TGA ATA AGT CAA CCA that a protein, possibly associated with ribosomal stability, AGG- 39, cf (exons 6–9): 59 -ACA AGA AGA TGC ACA GAG CC- 39, cr: 59 -ACC TAG ATT GCA TAA GGT GTG- 39,df can be linked to X linked mental retardation (XLMR). http://jmg.bmj.com/ (exons 10 and 11): 59 -CCT GAC CTT GTC CTC AGT TG- 39, dr: 59 -CAT AAA GGT TGC CTT ACT CAA AC- 39. At the cDNA level the coding sequence was amplified with primer pair c1F: 59 -AGG TGG TAG CCC ATT CAT CTG- 39 and c1R: 59 -CTT ental retardation is the most frequent cause of serious GTT TGT CCA GGC CTC GTT G- 39 and sequenced according handicap in children and young adults. The under- the above described method. A total of 100 X chromosomes lying causes of this heterogeneous condition are both from unrelated healthy males and 200 X chromosomes from M 1 on September 23, 2021 by guest. Protected copyright. acquired and genetically based. In the case of X linked 100 unrelated healthy females were tested for the absence of mental retardation (XLMR), the prevalence has been the mutation by DHPLC analysis (WAVE, Transgenomics, estimated to be 1 in 500 males. More than 200 different Omaha, NE, USA) under the following conditions: gradient XLMR entities have been described so far.2–4 Of these, 140 of B buffer: 51–61%, running temperature: 65˚C. For PCR have been classified as syndromic forms characterised by amplification the following primer pair was used: wa_f: 59 - specific clinical, biochemical, or neurological features asso- CAC GGG CAG TTG ACC TGT G- 39 and wa_r: 59 -GGC CTT ciated with mental retardation. In contrast to this, non- CAC CCA GGA TAT AC- 39. Heteroduplex conformation was syndromic XLMR families (MRX) are characterised by made possible by adding female wildtype DNA to DNA from impairment of cognitive functions with no additional hemizygous males. features. A total of 81 MRX families have been reported so far, with partly overlapping linkage intervals.4 Although Northern analysis knowledge about the genetic causes of cognitive impairment cDNA of the FTSJ1 gene was radiolabelled using the Random has increased during the last few years and the first genes Primed DNA Labeling Kit (Roche Diagnostics) and hybridised responsible for non-syndromic mental retardation have been to membranes containing human multiple tissue cDNA described,5 the total number of genes involved in MRX is still panels (MTC panels from Clontech Laboratories, Palo Alto, a matter of debate.46 CA, USA). Hybridisation and washing of the membranes was Recently, our group has refined the linkage interval of a performed using ExpressHyb hybridisation solution large Belgian MRX family classified as MRX9,7 from Xp21– (Clontech) according to the recommendation of the manu- q13 to Xp11.4–Xp11.22.8 This four-generation family consists facturers. of seven affected males, their five non-affected brothers, and five carrier females (fig 1). Patients were diagnosed as Abbreviations: SAM, S-adenosylmethionine; XLMR, X linked mental affected with mild to severe mental retardation with no retardation www.jmedgenet.com 680 Ramser, Winnepenninckx, Lenski, et al J Med Genet: first published as 10.1136/jmg.2004.019000 on 1 September 2004. Downloaded from Figure 1 Pedigree of the MRX9 family. Affected males are indicated by black boxes, the obligate carrier females with dotted circles. Affected and unaffected family members tested for the mutation are indicated with an arrow. RESULTS (fig 2A). Genomic sequence analysis of an affected male All known MRX and MRXS genes in the MRX9 linkage (IV-1, fig 1) revealed an A.G substitution in the acceptor interval were excluded as candidate genes (data not shown). consensus splice site in intron 3 (IVS3-2A.G) in a human In order to identify a novel gene for MRX, a complete gene homologue of the bacterial Ftsj gene,9 the FTSJ1 gene (fig 3). catalogue was established for the 11.3 Mb large refined This gene is located in Xp11.23, proximal to DXS6949 and linkage interval between markers DXS228 and DXS1204 and distal to DXS6941, between the SN2 and PPN genes (fig 2A). mutation analysis of 23 selected candidate genes was The mutation segregates with the mental retardation in the performed on genomic DNA and/or at the cDNA level family, in fact it was found in all affected individuals (III-4, AB IPP2H (XM_018008) MAOB MAOB (NM_000898) FLJ22843 (NM_025184) Hs: MGRTSKDKRDVYYRLAKENGWRARSAFKLLQLDKEFQLFQGVTRA--VDLCAAPGSWSQVLSQKIGG-- Mm: MGRTSKDKRDVYYRLAKENGWRARSAFKLLQLDEEFQLFKGVKRA--VDLCAAPGSWSQVLSQKVGG-- MGC51029 (NM_17394) Rn: MGRTSKDKRDVYYRLAKEKGWRARSAFKLLQLDEEFQLFKGVKRA--VDLCAAPGSWSQVLSQKVGG-- Dm: MGKTSKDKRDIYYRQAKDEGWRARSAFKLLHVDEAYGILNGVQRA--VDLCAAPGSWSQVLSRKLYDTC LMWDSP21(NM_022076) Ce: MGKTSRDKRDIYYRLAKENKWRARSAFKLMQIDDEFQILKGVRRA--VDLCAAPGSWSQVLSKRLYE-- UTX (NM_021140) Sc: MGKSSKDKRDLYYRKAKEQGYRARSAFKLLQLNDQFHFLDDPNLKRVVDLCAAPGSWSQVLSRKLFD-E DXS1003 http://jmg.bmj.com/ KIAA0215 (NM_014735) Hs: -----QGSGHVVAVDLQAMAPLPGVVQIQGDITQLSTAKEIIQHFKG---CPADLVVCDGAPDVTGLHD Mm: -----QGSGQVVAVDLQAMAPLPGVIQIQGDITQLSTAKEIIQHFEG---CPADLVVCDGAPDVTGLHD p11.3 RGN (NM_004683) Rn: -----QSSGQVVAVDLQAMAPLPGVIQIQGDITQLSTAKEIIQHFEG---CPADLVVCDGAPDVTGLHD Dm: ETDDEKSAVKIIAVDLQAMAPIRGILQLQGDITKQSTAEAIIGHF--GGNEKAQLVVCDGAPDVTGVHE P17.3 (NM_019056) Ce: ----EDQEAKIVAIDLQPMAPIPGVIQLQGDITSVDTANQVIKHFSG---EKSDIVICDGAPDVTGIHS PCTK1 (NM_006201) Sc: SPSSDKEDRKIVSVDLQPMSPIPHVTTLQADITHPKTLARILKLF---GNEKADFVCSDGAPDVTGLHD ZNF157 (NM_003446) Hs: VDEYMQAQLLLAALNIATHVLKPGGCFVAKIFRGRDVTLLYSQLQVFFSSVLCAKPRSSRNSSIEAFAV Mm: VDEYMQAQLLLAALNIATHVLKLGGCFVAKIFRGRDVTLLYSQLRIFFSSVLCAKPKSSRNSSIEAFAV ZNF41 (NM_007130) Rn: VDEYMQAQLLLAALNIATHVLKPGGCFVAKIFRGRDVTLLYSQLRIFFSSVLCAKPKSSRNSSIEAFAV Dm: MDEYMQHQLLVAALSIATCVLETGGTFVAKIFKGNATSLLSSQMQIFFKKFDIYKPPSSRPSSIEAFVV on September 23, 2021 by guest. Protected copyright. TIMP1 (NM_003254) Ce: LDEFMQAELILAAFNITSHVLKEGGNFLAKIFRSRNSSLLYAQMKKYFKKVYLAKPRSSRQSSCEAFVL ELK1 (NM_005229) Sc: LDEYVQQQLIMSALQLTACILKKGGTFVAKIFRGRDIDMLYSQLGYLFDKIVCAKPRSSRGTSLEAFIV UXT (NM_004182) Hs: CQGYDPPEGFIPDLSKPLLDHSY.. Mm: CQGYDPPEGFIPDLTRPLLNHSY.. SN2 (033518) Rn: CQGYDPPEGFIPDLTRPLMNHSY.. DXS6949 Dm: CSDFCLPEGYIPQVINPARDDIR.. DXS6941 FTSJ1 (NM_012280) Ce: CLDYSPPEGFVPTMGKTSLDATD.. PPN (NM_022825) Sc: CLGYNPPSNWTPKLDVNTSVDEF.. p11.23 EBP (NM_006579) MG81 (XM_047025) RBM3 (NM_006743) Genes recently associated with MRX DXS722 WDR13 (NM_017883) SUV39H1 (NM_003173) PQBP1 (NM_005710) Figure 2 (A) Genes in the refined linkage interval screened for mutations. Genes recently associated with MRX are indicated with a red star. (B) Protein alignment of the FTSJ domain (highlighted in red) in the FTSJ1 protein of various species, showing conservation of the domain. Ce, Caenorhabditis elegans; Dm, Drosophila melanogaster; Hs, Homo sapiens; Mm, Mus musculus; Rn, Rattus norvegicus; Sc: Saccharomyces cerevisiae. The abrogated part of the protein caused by the mutation is highlighted in green. www.jmedgenet.com A mutation in the FTSJ1 gene is associated with mental retardation 681
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