<abstract xmlns="http://www.w3.org/1999/xhtml">

<bold>Objective.</bold> Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3–4% of patients, thus exceeding the prevalence in the general population. HH association is stronger for KS type 2 (KDM6A-KS, OMIM #300867) than KS type 1 (KMT2D-KS, OMIM #147920). Both the disease-associated genes, KMD6A and KMT2D, modulate the chromatin dynamic. As such, KS is considered to be the best characterized pediatric chromatinopathy. However, the exact pathogenetic mechanisms leading to HH in this syndrome remain still unclear.
<bold>Methods.</bold> We selected on the electronic database PubMed all articles describing or hypothesizing the mechanisms underlying the dysregulated insulin secretion in KS.
<bold>Results.</bold> The impact on the gene expression due to the KDM6A or KMT2D function loss may lead to a deregulated pancreatic β-cell differentiation during embryogenesis. Moreover, both KMT2D gene and KDM6A gene are implicated in promoting the transcription of essential pancreatic β-cell genes and in regulating the metabolic pathways instrumental for insulin release. Somatic KMT2D or KDM6A mutations have also been described in several tumor types, including insulinoma, and have been associated with metabolic pathways promoting pancreatic cell proliferation.
<bold>Conclusions.</bold> The impact of pathogenic variants in KDM6A and KDM2D genes on β-cell insulin release remains to be fully clarified. Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.
</abstract>

Objective. Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3–4% of patients, thus exceeding the prevalence in the general population. HH association is stronger for KS type 2 (KDM6A-KS, OMIM #300867) than KS type 1 (KMT2D-KS, OMIM #147920). Both the disease-associated genes, KMD6A and KMT2D, modulate the chromatin dynamic. As such, KS is considered to be the best characterized pediatric chromatinopathy. However, the exact pathogenetic mechanisms leading to HH in this syndrome remain still unclear.
Methods. We selected on the electronic database PubMed all articles describing or hypothesizing the mechanisms underlying the dysregulated insulin secretion in KS.
Results. The impact on the gene expression due to the KDM6A or KMT2D function loss may lead to a deregulated pancreatic β-cell differentiation during embryogenesis. Moreover, both KMT2D gene and KDM6A gene are implicated in promoting the transcription of essential pancreatic β-cell genes and in regulating the metabolic pathways instrumental for insulin release. Somatic KMT2D or KDM6A mutations have also been described in several tumor types, including insulinoma, and have been associated with metabolic pathways promoting pancreatic cell proliferation.
Conclusions. The impact of pathogenic variants in KDM6A and KDM2D genes on β-cell insulin release remains to be fully clarified. Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.

A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome

CIBIO - Department of Cellular, Computational and Integrative Biology

Endocrine Regulations

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Objective. Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3–4% of patients, thus exceeding the prevalence in the general...

A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome

Data publikacji: 07 cze 2023

Zakres stron: 128 - 137

DOI: https://doi.org/10.2478/enr-2023-0016

Słowa kluczowe
Kabuki syndrome, hyperinsulinism, hypoglycemia, KMT2D, KDM6A, review

© 2023 Evelina Maines et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome

Data publikacji: 07 cze 2023

Zakres stron: 128 - 137

DOI: https://doi.org/10.2478/enr-2023-0016

Słowa kluczoweKabuki syndrome, hyperinsulinism, hypoglycemia, KMT2D, KDM6A, review

© 2023 Evelina Maines et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Słowa kluczowe
Kabuki syndrome, hyperinsulinism, hypoglycemia, KMT2D, KDM6A, review