title: The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome.
abstract: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder, characterized by exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow (BM) dysfunction with an increased risk to develop myelodysplastic syndrome and/or acute myeloid leukaemia (MDS/AML). SDS is caused, in nearly 90% of cases, by two common mutations (that is, c.183_184TA>CT and c.258+2T>C) in exon 2 of the SBDS gene, localized on chromosome 7. Clonal chromosome anomalies are often found in the BM of SDS patients; the most frequent is an isochromosome for long arms of chromosome 7, i(7)(q10). We studied eight patients with SDS carrying the i(7)(q10) who were compound heterozygotes for SBDS mutations. By assessing the parental origin of the i(7)(q10) using microsatellite analysis, we inferred from the results which mutation was present in double dose in the isochromosome. We demonstrate that in all cases the i(7)(q10) carries a double dose of the c.258+2T>C, and we suggest that, as the c.258+2T>C mutation still allows the production of some amount of normal protein, this may contribute to the low incidence of MDS/AML in this subset of SDS patients.
authors.affiliation: Genetica Medica, Fondazione IRCCS Policlinico San Matteo Università di Pavia e, Pavia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Minelli
authors.forename: E
authors.initials: E
authors.lastname: Maserati
authors.forename: E
authors.initials: E
authors.lastname: Nicolis
authors.forename: M
authors.initials: M
authors.lastname: Zecca
authors.forename: L
authors.initials: L
authors.lastname: Sainati
authors.forename: D
authors.initials: D
authors.lastname: Longoni
authors.forename: F
authors.initials: F
authors.lastname: Lo Curto
authors.forename: G
authors.initials: G
authors.lastname: Menna
authors.forename: F
authors.initials: F
authors.lastname: Poli
authors.forename: E
authors.initials: E
authors.lastname: De Paoli
authors.forename: M
authors.initials: M
authors.lastname: Cipolli
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.forename: F
authors.initials: F
authors.lastname: Pasquali
authors.forename: C
authors.initials: C
authors.lastname: Danesino
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D006579:Heterozygote; D006801:Humans; D007223:Infant; D018404:Isochromosomes; D015470:Leukemia, Myeloid, Acute / Q000209:etiology; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology*; D011506:Proteins / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D011506:Proteins; C470521:SBDS protein, human