Mελέτη της γενετικής βάσης της αναιμίας Diamond-Blackfan και του συνδρόμου Shwachman-Diamond στον ελληνικό πληθυσμό

Doctoral Dissertation uoadl:1326809 241 Read counter

Τομέας Υγείας - Μητέρας - Παιδιού
Library of the School of Health Sciences
Deposit date:
Delaporta Polyxeni
Dissertation committee:
Αντώνης Καττάμης, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Αριάδνη Καλπίνη-Μαύρου Καθηγήτρια, Ιατρική, ΕΚΠΑ
Λυδία Κόσσυβα Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Χριστίνα Κανακά –Geintenbein, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Μαρία-Ροζέ Πονς-Ροντρίγκεθ, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ιωάννα Traeger – Συνοδινού, Αναπληρώτρια Καθηγήτρια, Ιατρική, ΕΚΠΑ
Σοφία Κίτσιου – Τζέλη, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Original Title:
Mελέτη της γενετικής βάσης της αναιμίας Diamond-Blackfan και του συνδρόμου Shwachman-Diamond στον ελληνικό πληθυσμό
Introduction: Diamond Blackfan Anemia (DBA) and Shwachman Diamond Syndrome (SDS) are inherited bone marrow failure syndromes. DBA is a rare ribosomopathy characterized by normochromic macrocytic anemia, reticulocytopenia and absence or insufficiency of erythroid precursors in normocellular bone marrow, frequently associated with somatic malformations. Mutations in ribosomal genes account for 60% to 70% of DBA cases. Shwachman-Diamond syndrome (SDS) is an inherited neutropenia syndrome associated with a significant risk of aplastic anemia and malignant transformation. Multiple additional organ systems, including the pancreas, liver, and skeletal and central nervous systems, are affected. Mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene are present in most patients. Seventy five per cent of the causative mutations concern gene recombination events between SBDS gene and SBDSP pseudogene on chromosome 7. This study presents findings from 18 patients recorded in the Greek DBA registry and from eleven patients recorded in the Greek SDS registry.
Methods: Clinical evaluation of patients and data collection was performed followed by the molecular analysis of RPS19, RPL5, and RPL11 genes for DBA and SBDS gene for SDS. Mutation detection included PCR amplification, ECMA analysis, RFLPs and direct sequencing. To elucidate cis/ trans configuration of mutations on the SBDS gene double digestion with both AciI and Bsu36I was performed. Restriction Fragment Length Polymorphism assays with Bsu36I and AciI allowed detection of the two most common mutations (c.183-184 TA>CT and 258+2T>C).
Congenital anomalies were observed in 72% of the DBA patients. Three patients (17%) were found to carry mutations on the RPS19 gene, three patients (17%) on the RPL5 gene and one patient (6%) on the RPL11 gene. Mutations c.C390G (p.Y130X) and c.197_198insA (p.Y66X) detected in the RPL5 gene were novel.
Extreme clinical heterogeneity was documented and was attributed to both mosaicism and allelic expression. The most severely affected patient in our registry was diagnosed at birth and it is the first ever reported patient that required bone marrow transplantation so early in life. Severe psoriasis, a feature not previously reported in SDS, was observed in one patient. Mutations in SBDS gene were found in all patients. Cytogenetic analyses revealed two patients with, clonal abnormalities, one of which was novel.
Discussion: The clinical course both of DBA and SDS patients was similar to previous reports. The occurrence of thyroid carcinoma in an adult patient with DBA is the first to be reported in DBA. Also the results of our data support that SDS mode of inheritance can be very complex, mostly because of complicated gene conversions events. Mosaicism appears not to be rare in SDS and should be considered, especially in cases with clinical heterogeneity in the presence of similar genotypes.
Diamond-Blackfan Anemia, Shwachman-Diamond Syndrome, Ribosome, Gene conversion, SBDS
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