Publications

Authors:

Maguolo, Alice; Rodella, Giulia; Giorgetti, Alejandro; Nicolodi, Marion; Ribeiro, Rui; Dianin, Alice; Cantalupo, Gaetano; Monge, Irene; Carcereri, Sarah; De Bernardi, Margherita Lucia; Delledonne, Massimo; Pasini, Andrea; Campostrini, Natascia; Ion Popa, Florina; Piacentini, Giorgio; Teofoli, Francesca; Vincenzi, Monica; Camilot, Marta; Bordugo, Andrea

Title:

A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism

Year:

2022

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

GENES

ISSN of journal:

2073-4425

N° Volume:

13

Number or Folder:

2

Page numbers:

233-233

Keyword:

branched-chain amino acid metabolism; branched-chain ketoacid dehydrogenase kinase; genetic analysis; leucinosis; maple syrup urine disease; molecular dynamics simulations; newborn screening; whole-exome sequencing

Short description of contents:

: BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.

Product ID:

125341

Handle IRIS:

11562/1060191

Last Modified:

May 9, 2025

Bibliographic citation:

Maguolo, Alice; Rodella, Giulia; Giorgetti, Alejandro; Nicolodi, Marion; Ribeiro, Rui; Dianin, Alice; Cantalupo, Gaetano; Monge, Irene; Carcereri, Sarah; De Bernardi, Margherita Lucia; Delledonne, Massimo; Pasini, Andrea; Campostrini, Natascia; Ion Popa, Florina; Piacentini, Giorgio; Teofoli, Francesca; Vincenzi, Monica; Camilot, Marta; Bordugo, Andrea, A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism «GENES» , vol. 13 , n. 2 , 2022 , pp. 233-233

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