SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways

Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders.

Background and Objectives Inherited peripheral neuropathies (IPNs) are a group of genetic disorders of the peripheral nervous system in which neuropathy is the only or the most predominant clinical feature. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease. Autosomal recessive CMT (ARCMT) is generally more severe than dominant CMT and its genetic basis is poorly understood due to high clinical and genetic diversity. Here, we report clinical and genetic findings from 56 consanguineous Turkish families initially diagnosed with CMT disease. Methods We initially screened the GDAP1 gene in our cohort as it is the most commonly mutated ARCMT gene. Next, whole-exome sequencing and homozygosity mapping based on whole-exome sequencing (HOMWES) analysis was performed. To understand the molecular impact of candidate causative genes, functional analyses were performed in patient primary fibroblasts. Results Biallelic recurrent mutations in the GDAP1 gene have been identified in 6 patients. Whole-exome sequencing and HOMWES analysis revealed 16 recurrent and 13 novel disease-causing alleles in known IPN-related genes and 2 novel candidate genes: 1 for a CMT-like disease and 1 for autosomal recessive cerebellar ataxia with axonal neuropathy. We have achieved a potential genetic diagnosis rate of 62.5% (35/56 families) in our cohort. Considering only the variants that meet the American College for Medical Genetics and Genomics (ACMG) classification as pathogenic or likely pathogenic, the definitive diagnosis rate was 55.35% (31/56 families). Discussion This study paints a genetic landscape of the Turkish ARCMT population and reports additional candidate genes that might help enlighten the mechanism of pathogenesis of the disease.