Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

Abstract

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association with the activator domains of multiple cellular and viral transcriptional activators. Its exact physiological function in transcriptional regulation remains obscure. The CMT2B2-associated missense amino acid substitution p.A335V is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins. Furthermore, Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats. These results suggest a potential role of this protein in the molecular etiology of CMT2B2 and suggest a potential, more general role of MED25 in gene dosage sensitive peripheral neuropathy pathogenesis.

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

“…One family showed two separate segregating causes of CMT [Verny et al, 2004], one X-linked and the other caused by compound heterozygous mutations in MED25 . A novel, likely disease causing allele was found in trans with the only known disease causing allele in this gene [Leal et al, 2001; Leal et al, 2009]. In a proband with autosomal dominant neurosensory deafness and axonal neuropathy we found a recently reported mutation in MYH14 [Choi et al, 2011].…”

Homozygous MED25 mutation implicated in eye–intellectual disability syndrome

“…Mutation in MED25 was associated with axonal form of Charcot-Marie-Tooth disease type 2B2 in one study (Leal et al 2009). However, no additional cases have been described since the original publication in 2009 and further evidence is needed to prove that mutations in MED25 cause CMT2B2.…”

Homozygous missense mutation inMED25segregates with syndromic intellectual disability in a large consanguineous family

“…A single report of a large family associates the homozygous variant p.Ala335Val in MED25 with Charcot–Marie–Tooth disease type 2B2 (CMT2B2, OMIM #605589) 35. The variant attributed to CMT2 on MED25 (c.1004C>T) has a population frequency among Europeans (non-Finnish) of 1/160 (0.006042), which is quite large for a rare disease.…”