MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability

Abstract

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

“…In 1 additional family, we identified a novel disease-gene relationship, a new disease associated with a known gene, KIF1A, 14 and in 2 other families we identified the novel IPN genes, TBCK and MCM3AP. 13,19 Our diagnostic rate (24%) is within the 11% to 53% range of recently reported IPN cohorts ( Table 2) [4][5][6][7][8][9][10] ; and similar to the percentage of the total number of diagnoses in known genes in these IPN cohorts (29%; 102/354) ( Table 2). The wide range in diagnostic rates for these cohorts may be due to the use of different variant pathogenicity criteria and/or the number of genetic tests performed prior to WES; both make studies difficult to compare.…”

“…For example, interrogation of the WES data-set in this study resulted in 3 discoveries within our cohort; a novel disease associated with the gene KIF1A, 14 and 2 novel diseasecausing genes, TBCK and MCM3AP. 13,19 In all 3 of these cases, additional evidence, including identification of additional patients and functional studies, was necessary to support pathogenicity of the variants. Had we not conducted additional research in these 3 cases, one could presume that the genes would still have been published as cohorts and these families would have received diagnoses following Similarly, the identification of MORC2 in family #23 reported here was the result of a reanalysis of WES data that was several years old (Table 1).…”

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

“…They were born at full term to non-consanguineous Estonian parents following an unremarkable pregnancy. Their birth weights were relatively small (-1.75SD) but the length was We previously found a decrease in mRNA levels of MCM3AP in patient fibroblasts (2). We now assessed MCM3AP mRNA levels in the skin fibroblasts of the NL2, EST1 and EST2 patients by quantitative PCR (qPCR), normalized to Glyceraldehyde 3-phosphate dehydrogenase (GAPDH).…”

Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation

“…With great interest, we read the article by Ylikallio et al (2017) presenting the first cases with functional molecular analysis of MCM3AP-related Charcot-Marie-Tooth neuropathy (CMT) and mild intellectual disability. MCM3AP has first been proposed as a candidate disease-causing gene for intellectual disability, polyneuropathy and ptosis (Schuurs-Hoeijmakers et al, 2013).…”