title: A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype.
abstract: Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and post-natal growth retardation, dysmorphic facial features and body asymmetry. About 50% of the patients carry (epi)genetic alterations involving chromosomes 7 or 11.The high proportion of patients with unidentified molecular etiology suggests the involvement of other genes. Interestingly, SRS patients share clinical features with the 12q14 microdeletion syndrome, characterized by several deletions with a 2.6 Mb region of overlap. Among the genes present in this interval, high mobility AT-hook 2 (HMGA2) appears to be the most likely cause of the growth deficiency, due to its described growth control function. To define the role of HMGA2 in SRS, we looked for 12q14 chromosome imbalances and HMGA2 mutations in a cohort of 45 patients with growth retardation and SRS-like phenotype but no 11p15 (epi)mutations or maternal uniparental disomy of chromosome 7 (matUPD7). We identified a novel 7 bp intronic deletion in HMGA2 present in heterozygosity in the proband and her mother both displaying the typical features of SRS. We demonstrated that the deletion affected normal splicing, indicating that it is a likely cause of HMGA2 deficiency. This study provides the first evidence that a loss-of-function mutation of HMGA2 can be associated with a familial form of SRS. We suggest that HMGA2 mutations leading to haploinsufficiency should be investigated in the SRS patients negative for the typical 11p15 (epi)mutations and matUPD7.
authors: Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy.
authors: Agostina
authors: A
authors: De Crescenzo
authors: 1] Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy [2] Dipartimento di Biologia, Università di Napoli 'Federico II', Napoli, Italy.
authors: Valentina
authors: V
authors: Citro
authors: Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy.
authors: Andrea
authors: A
authors: Freschi
authors: 1] Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy [2] Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche CNR, Napoli, Italy.
authors: Angela
authors: A
authors: Sparago
authors: Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors: Orazio
authors: 0000000165833482
authors: O
authors: Palumbo
authors: Dipartimento di Biologia, Università di Napoli 'Federico II', Napoli, Italy.
authors: Maria Vittoria
authors: MV
authors: Cubellis
authors: Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors: Massimo
authors: M
authors: Carella
authors: UOSC Genetica Medica, AORN A. Cardarelli, Napoli, Italy.
authors: Pia
authors: P
authors: Castelluccio
authors: UOSC Genetica Medica, AORN A. Cardarelli, Napoli, Italy.
authors: Maria Luigia
authors: ML
authors: Cavaliere
authors: Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy.
authors: Flavia
authors: F
authors: Cerrato
authors: 1] Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche (DISTABIF), Seconda Università degli Studi di Napoli, Caserta, Italy [2] Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche CNR, Napoli, Italy.
authors: Andrea
authors: A
authors: Riccio
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites; D017384:Sequence Deletion; D056730:Silver-Russell Syndrome / Q000235:genetics*
chemical_list: D025743:HMGA2 Protein; D022821:RNA Splice Sites