The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach.

Larissa Brussa Reis,Patricia Ashton-Prolla,Andreia Carina Turchetto-Zolet,Maievi Fonini,Clévia Rosset

doi:10.3390/genes10110839

Larissa Brussa Reis, Patricia Ashton-Prolla + Show 3 more

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https://doi.org/10.3390/genes10110839

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Abstract

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1.

Highlights

Neurofibromatosis type 1 (NF1) (OMIM # 162200) is an autosomal dominant tumor predisposition syndrome affecting both sexes in all ethnic groups, with an estimated incidence of one per 3000 [1].NF1 results from dominant loss-of-function mutations mainly in the NF1 gene, but this is not the only mutational event that explains the phenotype
The results showed that three genes were found deleted in primate species, such as ATPase family AAA domain containing 5 (ATAD5) in Pongo abelli, ring finger protein 135 (RNF135) showed that three genes were found deleted in primate species, such as ATAD5 in Pongo abelli, in Nomascus leucogenys, and leucine rich repeat containing 37B (LRRC37B) in Callithrix Jacchus
The cytokine receptor like factor 3 (CRLF3), ATAD5, ADAP2, NF1, SUZ12, oligodendrocyte myelin glycoprotein (OMG), EVI2A, RAB11FIP4, TEFM, and CORPS genes did not present statistically significant values for the comparisons of M2 × M1 and M8 × M7 models, indicating that they may be under purifying selection (Table 1)

Summary

Introduction

Neurofibromatosis type 1 (NF1) (OMIM # 162200) is an autosomal dominant tumor predisposition syndrome affecting both sexes in all ethnic groups, with an estimated incidence of one per 3000 [1]. NF1 results from dominant loss-of-function (haploinsufficiency) mutations mainly in the NF1 gene, but this is not the only mutational event that explains the phenotype. The NF1 phenotype is extremely variable and one possible explanation for this variation is a large number of different mutations in different regions of the NF1 gene [3]. 20% of NF1 mutations are single or multiexon deletions or duplications; 5–10% of these NF1 deletions are known as microdeletions, surrounding NF1 and its bordering genes. Patients with microdeletions have been described to have a higher risk of malignant peripheral nerve sheath

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