Defective sumoylation pathway directs congenital heart disease

Abstract

Congenital heart defects (CHDs) are the most common of all birth defects, yet molecular mechanism(s) underlying highly prevalent atrial septal defects (ASDs) and ventricular septal defects (VSDs) have remained elusive. We demonstrate the indispensability of “balanced” post-translational SUMO conjugation-deconjugation pathway for normal cardiac development. Both hetero- and homo-zygous SUMO-1 knockout mice exhibited ASDs and VSDs with high mortality rates, which were rescued by cardiac re-expression of the SUMO-1 transgene. Since SUMO-1 was also involved in cleft lip/palate in human patients, the above findings provided a powerful rationale to question whether SUMO-1 was mutated in babies born with cleft palates and ASDs. Sequence analysis of DNA from newborn screening blood spots revealed a single 16 bp substitution in the SUMO-1 regulatory promoter of a patient displaying both oral-facial clefts and ASDs. Diminished sumoylation activity whether by genetics, environmental toxins and/or pharmaceuticals may significantly contribute to susceptibility to the induction of congenital heart disease worldwide.

The Ubiquitin-Like SUMO System and Heart Function

“…38 The SUMO-dependent regulation of these specific factors has been described in detail [39][40][41] but new findings in mouse models with alterations in the SUMO pathway provide a novel integrated view on SUMO function during embryonic development (Table). Interestingly, both hypo-or hyperSUMOylation because of dysfunction of either the conjugation or deconjugation system result in embryonic or cardiac defects, indicating that a tight control of the degree of SUMOylation is essential for normal cardiac development 44,54 (Table). Inhibition of SUMO conjugation by genetic inactivation of the SUMO-conjugating E2 enzyme Ubc9 causes early embryonic lethality in mice between embryonic stage 3.5 and embryonic stage 7.5, 42 demonstrating that attachment of SUMO is essential for embryonic viability (Table).…”

“…Despite its critical role in embryonic development, the SUMO2 KO mouse line does not show a specific cardiac phenotype, whereas the constitutive KO of SUMO1 led to specific cardiac septal defects (atrial septal defect and ventricular septal defect) with high penetrance. 44 The defects in SUMO1-mutant mice were rescued by transgenic cardiac-specific expression of SUMO1 arguing for an important and specific function of SUMO1 conjugation during normal cardiac development. 44 However, it is noteworthy that other groups failed to detect a phenotype in SUMO1 KO mice possibly because of differences in the genetic background and gene-targeting strategies.…”

“…44 The defects in SUMO1-mutant mice were rescued by transgenic cardiac-specific expression of SUMO1 arguing for an important and specific function of SUMO1 conjugation during normal cardiac development. 44 However, it is noteworthy that other groups failed to detect a phenotype in SUMO1 KO mice possibly because of differences in the genetic background and gene-targeting strategies. 45,46 The importance of a tightly regulated level of SUMOylation is also underlined by the observation of cardiac abnormalities in mice with cardiomyocyte-specific overexpression of the SUMO isopeptidase SENP2 (α-myosin heavy chain-SENP2-transgenic), 54 which decreases SUMO1 modification essentially mimicking the lack of SUMO1.…”

“…Additional candidates for critical targets of SUMO1 are serum responsive factor/myocardin or GATA4. 44,[59][60][61][62] It is worth noting that a subgroup of α-myosin heavy chain-SENP2-transgenic mice does not develop cardiac septal defects, but show cardiac hypertrophy and fibrosis (cardiomyopathy) during aging, indicating that balanced SUMOylation is also important for heart function in adult animals. 54 Because cardiac-specific overexpression of SUMO1-transgenic does only rescue the embryonic but not the adult heart phenotype of α-myosin heavy chain-SENP2-transgenic mice, it is tempting to speculate that enforced SENP2-mediated deconjugation of SUMO2/3 but not of SUMO1 primarily contributes to the adult phenotype.…”

“…43 At least in some pathological situations, enhanced modification by SUMO1 seems beneficial for cardiac function because cardiac-specific SUMO1-transgenic expression improved heart failure. 44,47 In contrast, cardiacspecific SUMO2 overexpression induces premature death and severe cardiomyopathy, although no obvious embryonic phenotype has been described. 50 SENP1 KO mice, another animal model for unbalanced SUMO deconjugation, exhibit embryonic lethality possibly because of persistent SUMO1 conjugation of hypoxia-inducible factor 1 alpha (HIF1α), which triggers its subsequent degradation followed by downregulation of the HIF1α target gene erythropoietin and defective erythropoesis.…”