Two patients with Canavan disease and structural modeling of a novel mutation

Abstract

Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme, which catalyzes the hydrolysis of N-acetyl-L-aspartate (NAA) into aspartate and acetate. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on two Egyptian patients diagnosed with CD, the first patient harbors five missense mutations (c.427 A > G; p. I143V, c.502C > T; p. R168C, c.530 T > C; p. I177T, c.557 T > C; p. V186D c.548C > T; p. P183L) and a silent mutation (c.693 C > T; p. Y231Y). The second patient was found to be homozygous for two missense mutations (c.427 A > G; p. I143V and c.557 T > A; p. V186D). Furthermore, molecular modeling of the novel mutation p. P183L provides an instructive explanation of the mutational impact on the protein structure that can affect the function of the ASPA. Here, the clinical, radiological, and biochemical profile of the two patients are reviewed in details.

Computational and Molecular Dynamics Simulation Approach To Analyze the Impact ofXPDGene Mutation on Protein Stability and Function

“…RMSD data imply that distinctly different type of deviation was noticed in the mutant protein throughout the entire simulation period as against native protein, thereby clearly demonstrating that mutation has a significant destabilizing effect on the protein. The association between the in-silico approach and wet lab experimentations has been rather evidenced by several previous studies [23,26]. Furthermore, computational mutation predictions when combined with MDS analysis has led to a breakthrough in the identification of most detrimental diseases causing mutations amid a huge pool of mutations [35].…”

“…XPD is a key NER enzyme that arbitrates in the transcription-coupled NER sub-pathway and can cause XP and other diseases when mutated in the germline [21]. However, recent advances in computational biology have afforded means to investigate genotype-phenotype correlation and their association with disease status [22][23][24][25][26]. Several bioinformatics algorithms used in combination frequently spotlight candidate functional missense mutations associated with genes [27][28][29][30][31].…”

An extensive computational approach to analyze and characterize the functional mutations in the galactose-1-phosphate uridyl transferase (GALT) protein responsible for classical galactosemia

“…The PredictSNP tool provides us with a prediction that is more accurate by integrating multiple algorithms of other pathogenicity testing tools [42]. We successfully used these in silico tools to examine the potential genotype and phenotype correlations in several genetic disorders in combination with simulation modeling and structural bioinformatics pipelines [43,[43][44][45][46][47][48]. Here, we used a combinatorial bioinformatics pipeline on the four missense mutations (Table 1 and Fig. 2(b)) and found p.S135L and p.Q188R cause the most pathogenic mutations and reduce protein stability, whereas p.K285N and p.N314D disrupted only the stability (Fig.…”

Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia

“…This is a common mechanism in many metabolic diseases [ 30 , 31 ]. They are also known to play a crucial role in maintaining the stability of the protein [ [32] , [33] , [34] , [35] , [36] ]. Proline amino acid is well studied as a potent secondary structure breaker of alpha-helices as well as the beta sheets [ 37 ].…”