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

Karakaya, Mert; Mazaheri, Neda; Polat, İpek; Bharucha‐Goebel, Diana; Donkervoort, Sandra; Maroofian, Reza; Shariati, Gholamreza; Hoelker, Irmgard; Monaghan, Kristin G.; Winchester, Sara; Zori, Robert; Galehdari, Hamid; Bönnemann, Carsten G.; Yış, Uluç; Wirth, Brunhilde

doi:10.1093/brain/awx222

Cited by 16 publications

(10 citation statements)

References 9 publications

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“…Although segregation of CMT with MCM3AP variants has previously been reported, the clinical features vary between the individuals in the present study and the previously reported. Unlike the previously reported cases with predominantly sensory motor CMT ( Karakaya et al , 2017 ; Ylikallio et al , 2017 ), finding from electromyography from the individuals with MCM3AP p.Ile954Thr variant indicated a motor axonal CMT with normal sensory conduction studies, although later in the disease course two of the patients developed distal sensory loss. In addition, clinical findings including intellectual disability were not present in affected individuals in this family.…”

Section: Discussioncontrasting

confidence: 91%

“…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…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Very recently the first cases of recessive CMT hereditary neuropathy, caused by variants in MCM3AP , have been reported ( Karakaya et al , 2017 ; Ylikallio et al , 2017 ; Kennerson et al , 2018 ). Affected individuals presented with severe childhood onset primarily axonal or demyelinating CMT neuropathy with mild-to-moderate intellectual disability ( Ylikallio et al , 2017 ), or sensorymotor polyneuropathy and distal weakness, with or without mild intellectual disability, strabismus and/or ophthalmoparesis ( Karakaya et al , 2017 ). Variants in MCM3AP were initially linked to intellectual disability in an affected sibling pair with progressive polyneuropathy ( Schuurs-Hoeijmakers et al , 2013 ) and later with a complex phenotype with immunodeficiency, genomic instability, skin changes and myelodysplasia in a child ( Gatz et al , 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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

Sedghi

Moslemi

Cabrera‐Serrano

et al. 2019

Brain Communications

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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.

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Section: Discussioncontrasting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sedghi

Moslemi

Cabrera‐Serrano

et al. 2019

Brain Communications

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“…Patients in this family had a relatively late age of onset and attacks were associated with a relatively minor drop in K + . Previously described bi‐allelic MCM3AP mutations, likely loss‐of‐function, have been reported to result in Charcot–Marie–Tooth neuropathy with distal weakness and mild intellectual disability . However, pleiotropy (mutations in 1 gene causing multiple different traits) is not uncommon as mutations in 1,274 genes have been reported to result in 2 or more phenotypes in the Online Mendelian Inheritance in Man database .…”

Section: Discussionmentioning

confidence: 99%

Family with primary periodic paralysis and a mutation in MCM3AP, a gene implicated in mRNA transport

2019

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Introduction: Primary periodic paralyses (PPs) are rare genetic neuromuscular disorders commonly caused by mutations in genes related to ion channel function. However, 10%–20% of cases remain as genetically unexplained. Herein we present a family with PP with paralytic episodes generally lasting for 1–7 days at a time, associated with a drop in K+ levels. Methods: Screening for mutations in known disease‐causing genes was negative, hence we performed whole‐exome sequencing of 5 family members. Results: Minichromosome maintenance 3–associated protein (MCM3AP) c.2615G>A (p.C872Y) was found to cosegregate with disease in the family and was not present in control subjects. The mutation is novel, highly conserved across multiple species, and predicted to be damaging. Discussion: MCM3AP encodes germinal center–associated nuclear protein (GANP), a protein involved in the export of certain messenger RNAs from the nucleus to the cytoplasm. Our findings suggest that a novel mutation in MCM3AP is associated with hypokalemic PP. Muscle Nerve, 2019

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Peripheral Nerve Disorders

Salih

Azzedine

2020

Clinical Child Neurology

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

Cited by 16 publications

References 9 publications

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

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

Family with primary periodic paralysis and a mutation in MCM3AP, a gene implicated in mRNA transport

Peripheral Nerve Disorders

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