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The Isochromosome I(7)(Q10) Carrying C.258&Plus;2T>C

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The Isochromosome I(7)(Q10) Carrying C.258&Plus;2T>C Leukemia (2009) 23, 708–711 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu ORIGINAL ARTICLE The isochromosome i(7)(q10) carrying c.258 þ 2t4c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome A Minelli1,10, E Maserati2,10, E Nicolis3,10, M Zecca4, L Sainati5, D Longoni6, F Lo Curto2, G Menna7, F Poli8, E De Paoli1, M Cipolli9, F Locatelli4, F Pasquali2 and C Danesino1 1Genetica Medica, Fondazione IRCCS Policlinico San Matteo Universita` di Pavia e, Pavia, Italy; 2Dipartimento Scienze Biomediche Sperimentali e Cliniche, Universita` dell’Insubria, Varese, Italy; 3Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University Hospital of Verona, Verona, Italy; 4Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Universita` di Pavia, Pavia, Italy; 5Clinica di Oncoematologia Pediatrica, Universita` di Padova, Padova, Italy; 6Clinica Pediatrica Universita` Milano-Bicocca, OC San Gerardo, Monza, Italy; 7Dipartimento di Oncologia AORN Santobono Pausilipon, Napoli, Italy; 8Clinica Pediatrica IRCCS Burlo Garofolo, Universita` di Trieste, Trieste, Italy and 9Cystic Fibrosis Center, Verona, Italy Shwachman–Diamond syndrome (SDS) is an autosomal reces- 20, del(20)(q11). Recently, Shimamura3 reviewed available sive disorder, characterized by exocrine pancreatic insuffi- evidence that patients with the i(7)(q10) should be considered ciency, skeletal abnormalities and bone marrow (BM) dysfunction with an increased risk to develop myelodysplastic as a separate group in terms of prognosis, as, in comparison to syndrome and/or acute myeloid leukaemia (MDS/AML). SDS is patients with different chromosome 7 anomalies, such as caused, in nearly 90% of cases, by two common mutations (that monosomy or deletion of the long arms, they have a lower risk is, c.183_184TA4CT and c.258 þ 2T4C) in exon 2 of the SBDS of MDS/AML. gene, localized on chromosome 7. Clonal chromosome anoma- Most SDS patients carry at least one of the two most common lies are often found in the BM of SDS patients; the most mutations of the SBDS gene, in exon 2: c.183_184TA4CT and frequent is an isochromosome for long arms of chromosome 7, þ 4 i(7)(q10). We studied eight patients with SDS carrying the c.258 2T C; the first one introduces an in-frame stop codon i(7)(q10) who were compound heterozygotes for SBDS muta- (p.K62X), whereas the second one disrupts the donor splice site 2 tions. By assessing the parental origin of the i(7)(q10) using of intron 2 and results in a truncated protein. Other rarer microsatellite analysis, we inferred from the results which mutations were recently reviewed by Costa and Santos.4 The mutation was present in double dose in the isochromosome. SBDS gene, highly conserved throughout evolution, encodes a We demonstrate that in all cases the i(7)(q10) carries a double 250 amino-acid protein with no homology to other proteins of dose of the c.258 þ 2T4C, and we suggest that, as the known function. This protein was shown to be relevant for c.258 þ 2T4C mutation still allows the production of some amount of normal protein, this may contribute to the low ribosome biogenesis and, more recently, also for stabilization of 5 incidence of MDS/AML in this subset of SDS patients. the mitotic spindle. A reduced but detectable quantity of the Leukemia (2009) 23, 708–711; doi:10.1038/leu.2008.369; SBDS protein was shown to be present in fibroblasts of two SDS published online 15 January 2009 patients, this finding suggesting that the mutation found in these Keywords: Shwachman–Diamond syndrome; isochromosome 7q; two cases, namely c.258 þ 2T4C, may lead to the presence of ; MDS/AML risk SBDS a small amount of alternatively spliced SBDS mRNA, encoding a functional protein.6 Recently, Nicolis et al.7 demonstrated that wild-type (wt) mRNA can be found in patients carrying this mutation. Introduction To evaluate whether the mutations of the SBDS gene carried by i(7)(q10) have different roles in promoting the development of Shwachman–Diamond syndrome (SDS) is an autosomal reces- MDS/AML, we investigated the parental origin of the i(7)(q10) in sive disorder (OMIM 260400), characterized by exocrine the BM of eight patients, and, as all of them were compound pancreatic insufficiency, skeletal abnormalities and bone heterozygotes for SBDS mutations, we inferred from the result marrow (BM) dysfunction, with a risk, as high as 30%, to which mutation was present in double dose in the isochromosome. develop myelodysplastic syndrome and/or acute myeloid leukaemia (MDS/AML).1 The SBDS gene (OMIM 607744) is localized on chromosome 7 at the band q11 and mutations of Material and methods this gene are found in 90% of patients.2 Clonal chromosome anomalies are often found in the BM of We retrospectively selected a cohort of eight SDS patients in SDS patients, often involving chromosomes 7 and 20, the most whom: (i) the clinical diagnosis was confirmed by mutation frequent being an isochromosome for the long arms of analysis and (ii) the cytogenetic studies demonstrated the chromosome 7, i(7)(q10), and a deletion of the long arms of a presence of i(7)(q10) in 20–100% mitoses from BM. Clinical characteristics, as well as essential data on cytogenetics and Correspondence: Professor C Danesino, Genetica Medica, Universita` follow-up, are detailed in Table 1. No patient ever showed signs di Pavia, Via Forlanini 14, 27100 Pavia, Italy. of overt transformation into MDS/AML, including those with the E-mail: [email protected] 10These three authors contributed equally to this work. longest follow-up (nos 1–3 and 5). All patients were compound Received 25 July 2008; revised 20 October 2008; accepted 24 heterozygotes with the c.258 þ 2T4C mutation; the second November 2008; published online 15 January 2009 mutation was either the c.183_184TA4CT or the c.258 þ 2T4C mutation in i(7)(q10) and risk of MDS/AML in SDS A Minelli et al 709 Table 1 Cohort of SDS patients enrolled in the study; none showed signs of overt MDS/AML Case BM cytogeneticsa Haematological follow-up/outcomeb Date Karyotype % i(7)(q10)+ cells 1 2 December 1997 46,XX,i(7)(q10) [30] 100 16 y/dead when 16-year-old due to BM aplasia 2 10 July 2001 46,XY,i(7)(q10) [20]/46,XY [10] 66 16 y/alive 3 18 November 2004 46,XX,i(7)(q10) [17]/46,XX [4] 81 27 y/alive 4 17 March 2006 46,XX,i(7)(q10) [16]/46,XX [21] 43 3.5 y/alive 5 23 March 2007 46,XY,i(7)(q10) [41]/46,XY [1] 98 21 y/alive 6 30 May 2007 46,XX,i(7)(q10) [15] 100 2.5 y/alive 7 18 September 2007 46,XY,i(7)(q10) [5]/46,XY [25] 20 3 y/alive 8 18 April 2008 46,XX,i(7)(q10) [7]/46,XX [6] 53 1 y/alive Abbreviations: AML, acute myeloid leukaemia; BM, bone marrow; MDS, myelodysplastic syndrome; SDS, Shwachman–Diamond syndrome. aResults of chromosome analyses at the date of sampling also for the molecular study. bFollow-up in years (y) from SDS diagnosis. Table 2 Results of molecular analysis demonstrating the parental origin of the i(7)(q10) Case Mutationsa Allele proportionFratiob Parental origin of iso(7)(q10) Short arm Long arm 1 Propositus: B/C FoMF4M Paternal Father: B Mother: C 2 Propositus: A/B MoFM4F Maternal Father: A Mother: B 3 Propositus: B/C MoFF0.47 (3) M4FF1.6 (3) Maternal Father: C Mother: B 4 Propositus: A/B FoMF0.73 (3) F4MF1.22 (4) Paternal Father: B Mother: A 5 Propositus: A/B FoMF0.68 (1) F4MF1.32 (2) Paternal Father: B Mother: A 6 Propositus: A/B FoMF0.54 (4) F4MF2.00 (3) Paternal Father: B Mother: A 7 Propositus: A/B FoMF0.53 (2) F4MF1.27 (1) Paternal Father: B Mother: A 8 Propositus A/B FoMF0.8 (2) F4MF1.41 (4) Paternal Father: A Mother: B Abbreviations: F, father; M, mother. aMutations are indicated by capital letters: A refers to the c.183_184TA4CT, B refers to c.258+2T4C and C refers to c.183_184TA4CT+258+2T4C. bThe number of STRP analysed is given in brackets. c.183_184TA4CT þ 258 þ 2T4C (Table 2). Some data on or migration time. The GenScanView 1.2/4 software provides cases 1–3 have been previously reported by Maserati et al.,8,9 peak detection (areas and heights) relative to alleles amplified as (unique patient number, UPN1) and Porta et al.10 (UPN25), DNA fragments. After the identification in each patient of respectively. Informed consent to be included in this study was the parental origin of the different STRPs tested, we compared obtained according to the principles of the Declaration of the height of the paternal and maternal alleles and Helsinki from patients or their parents. calculated the ratios between the allele coming from the parent Cytogenetic investigations were performed with routine carrying the c.258 þ 2T4C and that coming from his/her methods. Patients’ DNA was obtained from the same BM spouse, as this mutation is associated with the possibility of specimens used for chromosomal analysis; parental DNA was producing some amount of the wt protein. This method was also available for all cases. DNA extraction was performed with applied to case nos 3–8, whereas case nos 1 and 2 were studied GenElute Blood Genomic kit (Sigma, St Louis, MO, USA) and as reported by Maserati et al.8,9 mutation analysis was performed as reported by Nicolis et al.11 RNA analysis was performed in case nos 4 and 6 as reported We selected the short tandem repeat polymorphisms (STRPs) earlier.7 to be studied depending on their heterozygosity (always above 80%) and chromosomal mapping: D7S3048; D7S1808; D7S1818; D7S1830 (short arm) and D7S1820; D7S796; Results D7S2202; D7S1805 (long arm).
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