A Second Locus for an Axonal Form of Autosomal Recessive Charcot-Marie-Tooth Disease Maps to Chromosome 19q13.3

Abstract

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).

COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants

“…The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. MED25 was first implicated in the pathogenesis of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) [Leal et al, 2001[Leal et al, , 2009. However, recent studies suggest that the mutation implicated in CMT2B is likely to be a rare benign variant rather than pathogenic [Figueiredo et al, 2015].…”

Deciphering peripheral nerve myelination by using Schwann cell expression profiling

“…Another positional candidate for causing neuropathy based on this idea of complementation is Sirt2, which is a member of the Sir2 family of NAD-dependent histone deacetylase enzymes thought to regulate gene silencing, aging, and the cell cycle (34), is located at 19q13, and overlaps with the mapping of CMT2B2 at 19q13.3 (35), as well as a severe form of CMT4 at 19q13.1-q13.3 (36). Finally, AF1q, a transmembrane protein found to cause acute leukemia when fused with the protein MLL (mixed lineage leukemia) (37), also overlaps with the mapping of CMT2B1 at 1q21 (38).…”

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

“…1a). This refinement could be done since individual B-5.3 [17] agreed with his participation on this study.…”