Abstract
Mutations in the proliferating cell nuclear antigen (PCNA)-binding domain of the CDKN1C gene were recently identified in patients with IMAGe syndrome. However, loss of PCNA binding and suppression of CDKN1C monoubiquitination by IMAGe-associated mutations hardly explain the reduced-growth phenotype characteristic of IMAGe syndrome. We demonstrate here that IMAGe-associated mutations in the CDKN1C gene dramatically increased the protein stability. We identified a novel heterozygous mutation, c.815T>G (p.Ile272Ser), in the CDKN1C gene in three siblings manifesting clinical symptoms associated with IMAGe syndrome and their mother (unaffected carrier). PCNA binding to CDKN1C was disrupted in the case of p.Ile272Ser, and for two other IMAGe-associated mutations, p.Asp274Asn and p.Phe276Val. Intriguingly, the IMAGe-associated mutant CDKN1C proteins were fairly stable even in the presence of cycloheximide, whereas the wild-type protein was almost completely degraded via the proteasome pathway, as shown by the lack of degradation with addition of a proteasome inhibitor, MG132. These results thus suggested that the reduced-growth phenotype of IMAGe syndrome derives from CDKN1C gain-of-function due to IMAGe-associated mutations driving increased protein stability.
Highlights
IMAGe syndrome (OMIM 614732) was originally defined as an association of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies [1]
The clinical symptoms of patients with IMAGe syndrome strongly suggest that mutations in their CDKN1C gene are associated with gain-of-function of the CDKN1C protein, disruption of proliferating cell nuclear antigen (PCNA) binding and suppression of CDKN1C monoubiquitination do not directly correlate with the CDKN1C gain-of-function [9], and truncation mutants of CDKN1C lacking PCNA binding were identified in Beckwith-Wiedemann syndrome (BWS) patients (Figure 1A) [11,12]
We describe a novel mutation in the PCNA-binding domain of the CDKN1C gene in three Japanese siblings who manifest most of the IMAGe-associated symptoms: i.e., intrauterine growth restriction, adrenal hypoplasia congenita, and genital anomalies in males
Summary
IMAGe syndrome (OMIM 614732) was originally defined as an association of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies [1]. Mutations across the length of the CDKN1C gene have been identified in patients with Beckwith-Wiedemann syndrome (BWS), which is characterized by an over-growth phenotype and an association with certain cancers; loss-of-function of CDKN1C promotes cell proliferation giving rise to an over-growth phenotype [11,12]. The clinical symptoms of patients with IMAGe syndrome strongly suggest that mutations in their CDKN1C gene are associated with gain-of-function of the CDKN1C protein, disruption of PCNA binding and suppression of CDKN1C monoubiquitination do not directly correlate with the CDKN1C gain-of-function [9], and truncation mutants of CDKN1C lacking PCNA binding were identified in BWS patients (Figure 1A) [11,12]
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