Rare cause of xanthinuria: a pediatric case of molybdenum cofactor deficiency B.

Molybdenum cofactor is essential for the activity of multiple enzymes including xanthine dehydrogenase. Molybdenum cofactor deficiencies are rare inborn errors of metabolism. Clinically, they present with intractable seizures, axial hypotonia, and hyperekplexia. They further develop cerebral atrophy, microcephaly, global developmental delay and ectopia lentis. We report a 5-year-old female with clinically, biochemically and genetically confirmed molybdenum cofactor deficiency type B due to compound heterozygous pathogenic variants in the molybdenum cofactor synthesis 2 gene found on whole exome sequencing. The xanthine stones were a key clue towards diagnosis. No mutation was detected in XDH gene. Implementation of a low-purine diet, urine alkalization and hydration lead to a near complete decrease in stone burden. The patient received pyridoxine supplementation with improvement in energy levels and attentiveness. Despite reports of high mortality at a young age, our patient was 9 years old at the time of this writing. Molybdenum cofactor deficiencies should be considered in neonates with early-onset seizures, hypotonia, and feeding difficulties. Screening with serum uric acid levels and empiric treatment may be considered while awaiting genetic results.

K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome.

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca(2+) current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore-forming α1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology.

A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2.

Zinc finger-containing Gli proteins mediate responsiveness to Hedgehog (Hh) signaling, with Gli2 acting as the major transcriptional activator in this pathway in mice. The discovery of disease-associated mutations points to a critical role for GLI2 in human Hh signaling as well. Here, we show that human GLI2 contains previously undescribed 5' sequence, extending the amino-terminus an additional 328 amino acids. In vitro, transcriptional activity of full-length GLI2 is up to 30 times lower than that of GLI2DeltaN (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2DeltaN also exhibits potent transcriptional activity in vivo: overexpression in mouse skin leads to the formation of Hh-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive Hh signaling. The discovery of this additional, functionally relevant GLI2 sequence led us to re-examine several pathogenic human GLI2 mutants, now containing the entire amino-terminal domain. On the basis of the functional domains affected by the mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. Moreover, deletion of the amino-terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain is required for transcriptional repressor activity of pathogenic GLI2. Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2 and is essential for dominant-negative activity of a GLI2 mutant associated with human disease.