Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants.

Abstract

We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.

• Authors: Francisco Javier Cotrina-Vinagre, María Elena Rodríguez-García, Elena Martín-Hernández, Cristina Durán-Aparicio, Abraham Merino-López, Enrique Medina-Benítez, Francisco Martínez-Azorín
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 133 Issue 2 Pg. 201-210 (06 2021) ISSN: 1096-7206 [Electronic] United States
• PMID: 33707149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• COL1A2 protein, human
• Collagen Type I
• NBAS protein, human
• Neoplasm Proteins
• Procollagen-Proline Dioxygenase
• P4HB protein, human
• Protein Disulfide-Isomerases

Topics

• Child
• Child, Preschool
• Collagen Type I (genetics)
• Craniosynostoses (complications, genetics, pathology)
• Dwarfism (diagnostic imaging, genetics, pathology)
• Eye Abnormalities (complications, genetics, pathology)
• Fever (complications, genetics)
• Heterozygote
• Humans
• Hydrocephalus (complications, genetics, pathology)
• Infant
• Infant, Newborn
• Liver (diagnostic imaging, pathology)
• Liver Failure, Acute (complications, diagnostic imaging, genetics, pathology)
• Male
• Mutation (genetics)
• Neoplasm Proteins (genetics)
• Osteogenesis Imperfecta (complications, diagnostic imaging, genetics, pathology)
• Phenotype
• Procollagen-Proline Dioxygenase (genetics)
• Protein Disulfide-Isomerases (genetics)
• Exome Sequencing