Neonatal Diabetes in Patients Affected by Liang-Wang Syndrome Carrying KCNMA1 Variant p.(Gly375Arg) Suggest a Potential Role of Ca2+ and Voltage-Activated K+ Channel Activity in Human Insulin Secretion

Abstract

Liang-Wang syndrome (LIWAS) is a polymalformative syndrome first described in 2019 caused by heterozygous mutation of the KCNMA1 gene encoding the Ca2+ and voltage-activated K+ channel (BKC). The KCNMA1 variant p.(Gly356Arg) abolishes the function of BKC and blocks the generation of K+ current. The phenotype of this variant includes developmental delay, and visceral and connective tissue malformations. So far, only three cases of LWAS have been described, one of which also had neonatal diabetes (ND). We present the case of a newborn affected by LIWAS carrying the p.(Gly375Arg) variant who manifested diabetes in the first week of life. The description of our case strongly increases the frequency of ND in LIWAS patients and suggests a role of BK inactivation in human insulin secretion. The knowledge on the role of BKC in insulin secretion is very poor. Analyzing the possible mechanisms that could explain the association of LIWAS with ND, we speculate that BK inactivation might impair insulin secretion through the alteration of ion-dependent membrane activities and mitochondrial functions in β-cells, as well as the impaired intra-islet vessel reactivity.

Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang–Wang syndrome

“…13 However, the clinical features had a larger variability with regard to ataxia, tremor, epilepsy, dysmorphism and developmental and other features. 13 Moreover, our study 13 and another recent study by Mameli et al 14 suggest that type I diabetes may be another clinical feature of Liang-Wang syndrome. Interestingly, homozygous KCNMA1 variants were also reported, for example, p.(Y676Lfs*7) detected in two siblings with epilepsy, developmental delay and severe cerebellar atrophy, and p.(R458Ter) identified in a patient with paroxysmal dyskinesia, epilepsy, intellectual delay and corticospinal-cerebellar tract atrophy.…”

“…Interestingly, homozygous KCNMA1 variants were also reported, for example, p.(Y676Lfs*7) detected in two siblings with epilepsy, developmental delay and severe cerebellar atrophy, and p.(R458Ter) identified in a patient with paroxysmal dyskinesia, epilepsy, intellectual delay and corticospinal‐cerebellar tract atrophy 15,16 . To date, 19 pathogenic KCNMA1 variants have been reported to be associated with different neurological disorders in 42 patients 14,17‐20 . Three of them acted by GOF, nine by LOF and three without functional characterization.…”

“…15,16 To date, 19 pathogenic KCNMA1 variants have been reported to be associated with different neurological disorders in 42 patients. 14,[17][18][19][20] Three of them acted by GOF, nine by LOF and three without functional characterization. Moreover, three KCNMA1 variants were identified in patients, but functional studies suggest that they are benign polymorphism that have no direct cause-consequence relationship with the disease.…”

The long and winding road to personalized medicine in KCNMA1‐linked channelopathies revealed by novel variants associated with the Liang‐Wang syndrome

“…In addition to this broad spectrum of developmental and neurological features, previous work from the Authors of the present study also demonstrated that heterozygous LoF KCNMA1 variants (the G375R, in particular) can also cause severe visceral and cardiovascular malformations, bone dysplasia, and facial dysmorphic features, 10 a phenotype identified as the Liang‐Wang syndrome (OMIM #618729). Notably, the same variant has also been recently described in a newborn presenting with neonatal diabetes with persistent insulin‐dependent hyperglycemia, in addition to congenital facial and internal organs abnormalities, a result suggestive of a critical role for K Ca channels in controlling insulin release from pancreatic β‐cells 11 …”

“…Notably, the same variant has also been recently described in a newborn presenting with neonatal diabetes with persistent insulin-dependent hyperglycemia, in addition to congenital facial and internal organs abnormalities, a result suggestive of a critical role for K Ca channels in controlling insulin release from pancreatic βcells. 11 In addition to those heterozygous variants, two additional homozygous KCNMA1 variants (R458X, Y676fs), 12,13 predicted to result in truncated, less functional protein, have been each identified in two patients affected with seizures, severe developmental delay, and non-progressive cerebellar atrophy; as a result, a third phenotype is now described in OMIM as associated with KCNMA1 variants, described as cerebellar atrophy, developmental delay, and seizures (CADEDS; #617643).…”