Arrabal, L.; Muñoz-Pujol, G.; Martínez, I.M.; Gort, L.; García-Villoria, J.; Roldán, S.; Tort, F.; Ribes, A. Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations. Int. J. Mol. Sci.2023, 24, 12319.
Arrabal, L.; Muñoz-Pujol, G.; Martínez, I.M.; Gort, L.; García-Villoria, J.; Roldán, S.; Tort, F.; Ribes, A. Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations. Int. J. Mol. Sci. 2023, 24, 12319.
Arrabal, L.; Muñoz-Pujol, G.; Martínez, I.M.; Gort, L.; García-Villoria, J.; Roldán, S.; Tort, F.; Ribes, A. Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations. Int. J. Mol. Sci.2023, 24, 12319.
Arrabal, L.; Muñoz-Pujol, G.; Martínez, I.M.; Gort, L.; García-Villoria, J.; Roldán, S.; Tort, F.; Ribes, A. Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations. Int. J. Mol. Sci. 2023, 24, 12319.
Abstract
Background: Protein CCDC186 is involved in the maturation of dense core vesicles in the trans-Golgi network in neurons and endocrine cells. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in CCDC186 had previously been described. However, no functional studies in any of these two cases had been performed. Methods: Exome sequencing from one affected individual of each family was performed. In addition, Sanger sequencing of the parents and one of the affected siblings was also performed. CCDC186 protein was assessed in cultured fibroblasts or muscle tissue by western blot. Transcriptomic analysis was done by means of RNA sequencing. Results. We identified three patients from two gypsy families, unrelated to each other, with the same homozygous mutations in CCDC186 gene. Clinically, all patients presented with seizures, frontotemporal atrophy, hypomyelination, recurrent infections, and endocrine disturbances such as severe non ketotic hypoglycemia. Low levels of cortisol, insulin or growth hormone could only be verified in one patient. All of them had a neonatal onset and died between 7 months and 4 years of age. WES identified a homozygous variant in CCDC186 gene (c.2215C>T, p.Arg739Ter) in the index patients of both families. Protein expression studies demonstrated that the CCDC186 was practically undetectable in fibroblasts and muscle tissue. These observations correlated perfectly with the transcriptomic analysis performed in fibroblasts in one of the patients, which showed a significant reduction of CCDC186 mRNA levels. Conclusion. Our study provides functional evidence that mutations in this gene have a pathogenic effect on the protein and reinforces CCDC186 as a new disease-associated gene. In addition, mutations in CCDC186 could explain the combined endocrine and neurologic alterations detected in our patients
Keywords
CCDC186 mutations; seizures; hypomyelination; low levels of cortisol; low levels of insulin; growth hormone deficiency; hypoketotic hypoglycemia
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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