Research Article: Structural basis of the dominant inheritance of hypermethioninemia associated with the Arg264His mutation in the MAT1A gene

Date Published: June 01, 2020

Publisher: International Union of Crystallography

Author(s): Jiraporn Panmanee, Svetlana V. Antonyuk, S. Samar Hasnain.


Dominant inheritance of hypermethioninemia is caused by an Arg264His mutation in methionine adenosyltransferase. The mutation lowers the affinity for dimer–dimer interaction and enzymatic activity, which can be restored by chemical intervention.

Partial Text

Methionine adenosyltransferase (MAT) deficiency (OMIM 250850) is the most common cause of isolated persistent hypermethioninemia (IPH), which has been established as an inborn error of metabolism (Gaull & Tallan, 1974 ▸). MAT enzymes (EC catalyse the formation of S-adenosyl-l-methionine (SAMe) from methionine (Met) and adenosine triphosphate (ATP). MATs are found in all living organisms, with the exception of some intracellular parasites that obtain SAMe from their host (Sánchez-Pérez et al., 2004 ▸). Normal cellular function and survival require SAMe as a versatile molecule with roles ranging from gene expression to membrane fluidity (Finkelstein, 1990 ▸; Friedel et al., 1989 ▸; Lu, 2000 ▸; Mato et al., 1997 ▸). In mammalian cells, MATα1 and MATα2 are two variants of the catalytic subunit encoded by the MAT1A and MAT2A genes, respectively (Chamberlin et al., 1996 ▸; De La Rosa et al., 1995 ▸). MATα1 has 84% amino-acid sequence similarity to MATα2, despite their distinct kinetic properties and expression in distinct tissues. MATα1 is a liver-specific enzyme that is mainly found in mature hepato­cytes, while MATα2 is expressed in extrahepatic tissues including kidney, brain and heart and also in developing liver cells (Alvarez et al., 1993 ▸; Horikawa & Tsukada, 1992 ▸; Kotb & Geller, 1993 ▸). Patients with IPH have low levels of hepatic MAT (MATα1) activity, resulting in high levels of methionine in the blood plasma. Case reports of MATα1 deficiency were identified through newborn screening programmes where the activity of MATα2 in erythrocytes, lymphocytes and fibroblasts was found to be normal (Gahl et al., 1988 ▸; Gaull et al., 1981 ▸). Hepatic MAT deficiency is usually inherited as an autosomal recessive trait (Chamberlin et al., 1996 ▸, 2000 ▸; Mudd et al., 1995 ▸; Ubagai et al., 1995 ▸) or as the exceptional Arg264His (R264H) autosomal dominant mutation (Chien et al., 2005 ▸; Couce et al., 2008 ▸, 2013 ▸; Martins et al., 2012 ▸; Ubagai et al., 1995 ▸). Neurological problems, including demyelination, abnormal mental development and cognitive impairment, have been reported in severe cases of autosomal recessive IPH, while the majority of patients with a mild to moderate condition present no clinical manifestations (Chamberlin et al., 1996 ▸, 2000 ▸; Hazelwood et al., 1998 ▸; Kido et al., 2019 ▸; Tada et al., 2004 ▸; Sen et al., 2019 ▸). R264H is the most prevalent mutation found to cause IPH-associated MATα1 deficiency in newborn screening programmes, as reported in the USA (three of 13 cases), Spain (15 of 18 cases), Japan (14 of 24 cases), Portugal (all 12 cases) and Taiwan (three of 16 cases) (Couce et al., 2013 ▸; Martins et al., 2012 ▸; Nagao et al., 2013 ▸; Chadwick et al., 2014 ▸; Chien et al., 2005 ▸). IPH related to the R264H mutation is usually clinically benign in the early stages of life (Couce et al., 2013 ▸; Nagao et al., 2013 ▸); however, the discovery of a three-year-old girl with myelination abnor­malities and the severe vascular diseases reported in some cases related to this mutation suggest that clinical monitoring should be performed (Martins et al., 2012 ▸).




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