Universität zu Köln

Mayr, Simon Julius, Sass, Joern Oliver, Vry, Julia, Kirschner, Janbernd ORCID: 0000-0003-1618-7386, Mader, Irina, Hoevener, Jan-Bernd, Reiss, Jochen, Santamaria-Araujo, Jose Angel, Schwarz, Guenter ORCID: 0000-0002-2118-9338 and Gruenert, Sarah Catharina (2018). A mild case of molybdenum cofactor deficiency defines an alternative route of MOCS1 protein maturation. J. Inherit. Metab. Dis., 41 (2). S. 187 - 197. DORDRECHT: SPRINGER. ISSN 1573-2665

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Abstract

Molybdenum cofactor deficiency is an autosomal recessive inborn error of metabolism, which results from mutations in genes involved in Moco biosynthesis. Moco serves as a cofactor of several enzymes, including sulfite oxidase. MoCD is clinically characterized by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. Here we report a patient with an unusual late disease onset and mild phenotype, characterized by a lack of seizures, normal early development, a decline triggered by febrile illness and a subsequent dystonic movement disorder. Genetic analysis revealed a homozygous c.1338delG MOCS1 mutation causing a frameshift (p.S442fs) with a premature termination of the MOCS1AB translation product at position 477 lacking the entire MOCS1B domain. Surprisingly, urine analysis detected trace amounts (1% of control) of the Moco degradation product urothione, suggesting a residual Moco synthesis in the patient, which was consistent with the mild clinical presentation. Therefore, we performed bioinformatic analysis of the patient's mutated MOCS1 transcript and found a potential Kozak-sequence downstream of the mutation site providing the possibility of an independent expression of a MOCS1B protein. Following the expression of the patient's MOCS1 cDNA in HEK293 cells we detected two proteins: a truncated MOCS1AB protein and a 22.4 kDa protein representing MOCS1B. Functional studies of both proteins confirmed activity of MOCS1B, but not of the truncated MOCS1AB. This finding demonstrates an unusual mechanism of translation re-initiation in the MOCS1 transcript, which results in trace amounts of functional MOCS1B protein being sufficient to partially protect the patient from the most severe symptoms of MoCD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mayr, Simon Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Sass, Joern Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Vry, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirschner, Janbernd UNSPECIFIED orcid.org/0000-0003-1618-7386 UNSPECIFIED Mader, Irina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoevener, Jan-Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiss, Jochen UNSPECIFIED UNSPECIFIED UNSPECIFIED Santamaria-Araujo, Jose Angel UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED Gruenert, Sarah Catharina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-194907
DOI:	10.1007/s10545-018-0138-7
Journal or Publication Title:	J. Inherit. Metab. Dis.
Volume:	41
Number:	2
Page Range:	S. 187 - 197
Date:	2018
Publisher:	SPRINGER
Place of Publication:	DORDRECHT
ISSN:	1573-2665
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SULFITE OXIDASE DEFICIENCY; READING FRAMES; INBORN-ERRORS; BIOSYNTHESIS; IDENTIFICATION; GENE; MUTATIONS; METABOLISM; UROTHIONE; MECHANISM Multiple languages Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19490