A mild case of molybdenum cofactor deficiency defines an alternative route of MOCS1 protein maturation

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.

Alternative splicing of bicistronic MOCS1 defines a novel mitochondrial protein maturation mechanism

“…In this patient low amounts of MOCS1B protein (residues 425 -620 in splice type III) were able to produce approximately 1% of wildtype Moco levels leading to a mild patient phenotype (Mayr et al, 2018).…”

<p>Molybdenum Cofactor Deficiency: Mega Cisterna Magna in Two Consecutive Pregnancies and Review of the Literature</p>

“…2,[9][10][11] There is a classic form of the disease observed in the first weeks of life and an atypical one characterized by a late onset. 4,6,12,13 In the classical variant, patients manifest a crude facial phenotype with depressed hyperteloric eyes, elongated palpebral fissures and late-onset lens dislocation. 1,2,5 In addition, they have thickened lips and broad philtrum, thick cheeks, small nose and microcephaly.…”

“…14 A residual molybdenum cofactor enzymatic function can usually be found and all three MOCS genes had been involved in this variant. [12][13][14] Probably, there are other similar cases that have not been diagnosed due to their mild clinical symptoms that can be confused with other pathologies.…”

“…20 The molybdenum cofactor deficiency type C by mutation of the GPHN gene is one of the rarest and most severe of all (only one case described in the literature) and it has been demonstrated in cell cultures that the repeated administration of high doses of inorganic molybdenum can be effective only in the treatment of the disease caused by this gene. 1,11 On the other hand, the response to a lowmethionine diet has been poor in the case presented by Mayr et al (MOCS1 mutation, atypical variant), 12 but successful in the case reported by Huijimans et al (MOCS3 mutation, atypical variant) with an improvement of symptoms. 13 In some articles, labor induction is recommended before 37 WG or when lesions are observed in neurosonography for early initiation of treatment with cPMP.…”

The Persistent Generalized Muscle Contraction in Siblings with Molybdenum Cofactor Deficiency Type A

“…1,2 There are atypical reports of a milder and late-onset form depending on the degree of residual activity even if there are variants of MOCS1. 14,15 To improve early treatment, research into early diagnosis and the relationship between genotype and phenotype is required. 15 Because MoCD-A is a rare disease, we believe that accumulation of reports of its clinical course, including genetic mutations such as this, is necessary for further research.…”