Discussion
The molybdenum cofactor deficiency is an ultra-rare autosomal recessive
disease, characterized by rapidly progressive and severe neurological
damage, sometimes misdiagnosed as hypoxic-ischemic encephalopathy. The
clinical and molecular characteristics of molybdenum cofactor deficiency
due to the MOCS2 variant have been recently extensively reviewed
by Arican et al. (2019). The presented group encompassed 35 patients
with proven molecular etiology and 29 different pathogenic variants
identified in the MOCS2 gene.
Our proband’s history and clinical features are consistent with the
previous descriptions. That prompted us to test toward a deficiency of
molybdenum cofactor, while neonatal-onset, refractory epilepsy, feeding
difficulties, facial dysmorphism, and brain images were the most
suggestive phenotypic feature. This initial clinical diagnosis,
supported by undetectable serum uric acid, very low serum homocysteine,
and positive Sulfite dipstick results, was finally verified in
whole-exome sequencing analysis. It revealed a variant of unknown
significance in the MOSC2 gene. The homozygous variant
c.472_477del on MOCS2 deletes nucleotides ’CTTTTA’ from
chromosome5 52396264, which does not change frameshift in the
protein-coding sequence. It has been reported with an extremely low
frequency in the large population cohorts (GenomAD). This inframe
deletion in the non-repeat region can change the length of proteins and
disrupt protein function. This variant is classified as uncertain
significance according to the recommendation of the American College of
Medical Genetics (ACMG) and Association for Molecular Pathology (AMP)
guideline. The child’s clinical features were, however, highly
consistent with the disease. Additionally, taking into account the
homozygous state of this variant, we suggest as causative.
We have performed an analysis of the crystal structure of the human
molybdopterin synthase complex to support this statement. The Leu158,
Lys159 are localized at the end of the last helix of the catalytic
subunit, just before the 13 aa of the C-terminus. This region of the
molybdopterin synthase has dual functionality. It binds the sulfur
carrier subunit and the precursor Z. The alignment of the crystal
structure of human molybdopterin synthase with the one ofStaphylococcus aureus complexed with precursor Z reflects that
Lys159 corresponds to Leu116 of (S. aureus ) is essential residue
for proper binding of the precursor Z.
In consequence of the mutation, the Leu158 will be replaced by Ala160,
and Lys159 by Lys161. Luckily, the deleted Lys159 should be replaced by
Lys161, and thus it’s role can be preserved (similar replacement of the
key amino acid was observed for example in D-amino acid oxidase, where
Tyr314 repossess the function of the Tyr55, eliminated by the Tyr55Ala
mutation and modifies the enzyme-substrate specificity (Subramanian,
2014). Since the second one replaces the crucial lysine, one could
expect, that the precursor Z binding can still occur, however, the
protein-ligand affinity can be already modified. However, in this case,
the situation is more complicated. The second lysine residue (123 inS. aureus and 166 in human) is essential for precursor Z binding,
and this crucial residue is located at the C-terminus. It is highly
probable that the deletion of two residues can modify the position of
the second lysine.
Moreover, it will have consequences on the folding of the C-terminus and
can result in changes in binding affinity of the sulfur carrier subunit
to the catalytic one. Thus, the described deletion could have
significant consequences for both, the heterodimer and the active
complex formation, which may suggest another mechanism of pathogenicity
of c.472_477del variant in the MOCS2 gene. As results from
predictSNP have shown (Suppl. 2), no deletion analysis is possible, but
the report clearly indicates that any mutation in this area has
consequences. However, to verify, which functionality is mostly
disturbed, the precursor binding or carrier subunit binding, further
study has to be considered.