Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP

Abstract

Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.

Keywords: Charcot-Marie-Tooth; GANP; MCM3AP; multiple sclerosis; neuropathy.

Graphical Abstract

Figure 1

Pedigrees of the family with MCM3AP variant and clinical features. Affected individuals are represented with shaded symbols. Hands and feet deformities were shown in Case V:6. Wrist and finger drop, high arch and hammertoe deformity, are shown.

Figure 2

Brain MRI. Axial contrast-enhanced T2W MRI image of the brain of Cases V:6, V:1 and V:3. Case V:6 (A) Midline sagittal flair (B) and parasagittal T1+GAD images, at 27 years of age, show multiple high-signal foci in the corpus callosum and paraventricular space with enhancing. (C) Axial FLAIR image, at 29 years of age, shows bilateral periventricular high-signal foci. (D) Spinal cord atrophy is shown. Case V:3 (E, F) Axial FLAIR images, at the age of 39, show bilateral juxta cortical, periventricular and paraventricular high-signal foci and ventricular dilation due to brain atrophy. (G) Sagittal T2 weighted image shows confluent plaques in pons and medulla. (H) Axial T1 weighted image shows some black hole lesions in paraventricular space due to severe axonal injury and loss. (I) Faint enhancement after contrast media administration. Case V:4 (J) At the age of 42, axial FLAIR image shows right periventricular, and juxta cortical and left paraventricular high-signal foci. (K) Sagittal Flair image, at 44 years of age, shows periventricular and white matter lesions and involvement of pons.

Figure 3

Molecular genetics data. (A) Multiple sequence alignment of the p.Ile954Thr region of the MCM3AP amino acid sequence confirms that the substitution affects an evolutionarily conserved residue (shaded). (B) Sanger sequence analysis demonstrates the presence of a novel homozygous missense mutation in exon 11 in MCM3AP (c.2861T>C) in Cases V:6, V:1 and V:3 (arrow). The apparently asymmetric parents and siblings were heterozygous for the variant. (C) The schematic illustration of GANP protein, consisting of different sub-domains, including the Sac3 domain. The previously reported variants of MCM3AP are shown with black arrows (bold indicates homozygous variants) and the novel p.Ile954Thr variant reported here is shown with red arrow. Adapted from Karakaya et al. (2017) by permission of Oxford University Press