ATP7A Clinical Genetics Resource - A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

Abstract

ATP7A is a critical copper transporter involved in Menkes Disease, Occipital horn Syndrome and X-linked distal spinal muscular atrophy type 3 which are X linked genetic disorders. These are rare diseases and their genetic epidemiology of the diseases is unknown. A number of genetic variants in the genes have been reported in published literature as well as databases, however, understanding the pathogenicity of variants and genetic epidemiology requires the data to be compiled in a unified format. To this end, we systematically compiled genetic variants from published literature and datasets. Each of the variants were systematically evaluated for evidences with respect to their pathogenicity and classified as per the American College of Medical Genetics and the Association of Molecular Pathologists (ACMG-AMP) guidelines into Pathogenic, Likely Pathogenic, Benign, Likely Benign and Variants of Uncertain Significance. Additional integrative analysis of population genomic datasets provides insights into the genetic epidemiology of the disease through estimation of carrier frequencies in global populations. To deliver a mechanistic explanation for the pathogenicity of selected variants, we also performed molecular modeling studies. Our modeling studies concluded that the small structural distortions observed in the local structures of the protein may lead to the destabilization of the global structure. To the best of our knowledge, ATP7A Clinical Genetics Resource is one of the most comprehensive compendium of variants in the gene providing clinically relevant annotations in gene.

Keywords: ACMG classification; ATP7A; Database; Menkes disease; Variants.

Graphical abstract

Fig. 1

The variants were annotated based on the context of the (A) genomic loci, (B) the functionality, (C) Distribution by Disease for the Pathogenic and Likely Pathogenic variants and (D) ACMG classification.

Fig. 2

Distribution of pathogenic/likely pathogenic variants in ATP7A protein.

Fig. 3

Allele frequency distribution of pathogenic ATP7A variants in different population datasets. SAS, South Asian; NFE, Non-Finnish European; FIN, Finnish; EAS, Eastern Asian; AMR, American; AFR, African; OTH, Other; ALL, All Samples. 1KG_ALL, 1000 genomes. ESP6500si_ALL, ESP6500 All Samples.

Fig. 4

A. Heatmap of the stability predictions using 9 different tools, where tool 1–9 represents FoldX, Schrödinger-OPLS2005, Schrödinger-OPLS3, MOE, CUPSAT, mCSM, SDM, iMutant 2.0 and POPMUSIC. B. Apo form of the sixth soluble domain of ATP7A, the position of the A629P mutation is labeled and marked with spheres. C. RMSD of the WT (blue) and A629P (orange). D. Potential energies of the WT (blue) and A629P (orange). E and F. RMSF of WT and A629P throughout 50 ns MD simulations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

A. Structure of the actuator domain of ATP7A, position of the mutations is labeled and marked as spheres. B. RMSD of the WT (dark blue), R844C (orange), R844H (grey), P852L (yellow) and G876R (pale blue). C. Potential energies of the WT (dark blue), R844C (orange), R844H (grey), P852L (yellow) and G876R (pale blue). 5D-H. RMSF of WT, R844C, R844H, P852L and G876R respectively throughout 50 ns MD simulations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Structure of the nucleotide binding domain of the ATP7A, position of the mutation is labeled and marked with spheres. B. RMSD of the WT (dark blue) and V1180D (orange). C. Potential energies of the WT (dark blue), V1180D (orange). D and E. RMSF of WT and V1180D throughout 50 ns MD simulations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)