13 novel putative mutations in ATP7A found in a cohort of 25 Italian families

Abstract

ATP7A is a copper-transporting P-type adenosine triphosphatase whose loss of function leads to the Menkes disease, an X-linked copper metabolism multi-organ disorder (1 in 100.000 births). Here we document our experience with the ATP7A linked diseases in Italy. We analyzed the exonic structure of the ATP7A gene in 25 unrelated Italian families and studied the variants of unknown significance. We identified 22 different DNA alterations, 13 of which first reported in this study. The classical Menkes phenotype was present in 21 of the 25 families and was linked with highly damaging mutations (7 nonsense; 4 frame-shift; 2 small in-frame deletions, 2 splice site alterations, 2 gross deletions, and 1 gross duplication). Of the 4 cases with milder variants of the Menkes disease two had a missense mutation, one a leaky splice site alteration and one a nonsense mutation in exon 22. We determined in silico that all the mutations leading to the classical Menkes disease leave no residual activity of ATP7A including the apparently less severe in-frame deletions. Whereas milder forms of the disease are characterized by mutations that allow a limited residual activity of ATP7A, including the nonsense mutation observed.

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

“…The compendium of curated variants encompasses a total of 602 variant entries in the ATP7A gene. These variants were derived from a total of 64 publications [6] , [8] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] and encompassed variants reported from 17 countries. Of the total compendium of variants, a total of 404 variants were unique and a large majority of variants mapped to exons 18,18% (328/404), while a small number were intronic 12% (49/404), splicing 6.18% (25/404) and UTR 0...…”

“…OHS. It is observed that MD with milder form are characterized by mutations showing some residual activity while mutations with no residual activity manifested classical form of MD [41] .…”

Copper and copper nanoparticles toxicity and their impact on basic functions in the body

“…In contrast to the Wilson disease, where mutation is located on autosome, the Menkes disease is related to X chromosome so the disease is manifested in men with mutation in their chromosome or in a woman in X-linked recessive inheritance mode. In the Menkes disease, gene ATP7A for copper-transporting P-type ATPase is mutated (60,61). Various mutations can occur in the ATP7A gene resulting in the lack of the coded P-type ATPase in the Trans-Golgi Network, which is natural site, where it is active and the lack of the copper concentration in the Golgi apparatus follows (62).…”

Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease

“…The overall incidence is 1 in 100,000–250,000 births, grouping MD as an ultra-rare orphan disease [ 3 ]. Genetically, loss-of-function alterations in ATP7A , resulting from point mutations, short indel, large deletions, and duplications, account for all the cases reported to date [ 1 , 2 , 4 , 5 , 6 , 7 ]. The ATP7A protein facilitates the export of copper from non-hepatic tissues and delivers copper to the secretory pathway for incorporation into copper-dependent enzymes [ 6 ].…”