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Novel variant in CADM3 causes Charcot-Marie-Tooth disease
Abdoulaye Yalcouyé1,2, Adriana P Rebelo3, Lassana Cissé1
1Faculté de Médecine et d'Odontostomatologie, USTTB, Bamako, Mali.
Insights
This study identifies a new mutation in the CADM3 gene causing rare axonal Charcot-Marie-Tooth disease. The findings highlight the importance of genetic testing in diverse populations for this neuropathy.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- A rare axonal form of Charcot-Marie-Tooth disease has been linked to the CADM3 gene.
- Previous reports identified a recurrent mutation in Caucasian families.
Purpose of the Study:
- To identify novel causative mutations in the CADM3 gene.
- To investigate the genetic basis of Charcot-Marie-Tooth disease in underrepresented populations.
- To characterize the functional impact of a new CADM3 variant.
Main Methods:
- Whole exome sequencing was performed on patients and their relatives.
- Segregation analysis confirmed the disease-causing role of the identified variant.
- Functional assays assessed protein levels and structural changes.
Main Results:
- A novel missense variant (c.1102G>T; Gly368Cys) in CADM3 was identified in a Black African family and a Caucasian patient.
- The variant segregated with the disease in an autosomal dominant and sporadic pattern.
- Functional analysis revealed decreased membrane protein levels and altered protein structure.
Conclusions:
- This study expands the known genotype spectrum for CADM3-associated neuropathy.
- The findings underscore the necessity of genetic research in diverse ethnic groups, including African populations.
- A novel CADM3 mutation contributes to axonal Charcot-Marie-Tooth disease, emphasizing genetic heterogeneity.
Abstract:
CADM3 has been recently reported causing a rare axonal Charcot-Marie-Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with autosomal dominant and sporadic patterns, respectively. Eight patients and their relatives were enroled from both families. The mean age at diagnosis was 33.9 years, and walking difficulty was commonly the first symptom. Neurological examination showed distal muscle weakness and atrophy, sensory loss and foot and hand deformities. A high clinical variability was noted, but as seen in CADM3-associated neuropathy, symptoms were more pronounced in the arms in some patients. Nerve conduction studies showed no response in most of the examined nerves, and an axonal type of neuropathy, where recorded. Whole exome sequencing revealed a novel missense variant (c.1102G>T; Gly368Cys) in CADM3, segregating with the disease. Functional analyses showed a significant decrease in CADM3-Gly368Cys protein levels in the membrane and major structural changes in its predicted secondary structure. Therefore, we extend the genotype spectrum of CADM3, underlining the need for genetic studies in underrepresented populations like in Africa.
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