Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, ...mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B). ...Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A) were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss) presentation, instead of USH1B.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Xeroderma pigmentosum (XP) is a genetically and clinically heterogeneous disease, associated with an inherited defect in one of eight different genes (XPA to XPG and XPV). In addition to the early ...onset of the skin manifestations, the XP group A is marked by the presence of a mild to severe neural disorders which appear tardily and worsens with age. In this study, 9 patients with moderate clinical profile belonging to 6 XP families were recruited to determine the XPA mutational spectrum in Morocco, using the direct sequencing of the whole coding region of the XPA gene.
The genetic investigation of the XPA gene showed that 7 from 9 patients were homozygous for the c.682C>T, p.Arg228X mutation, while all their investigated family members were heterozygous. The frequency of this mutation was estimated to be 83.33% (5/6 families) .The molecular analysis of the 5 other exons of the XPA gene, showed that the 2 negative siblings carried no mutation in the XPA gene. This finding suggests that c.682C>T (p.Arg228X) mutation is relatively associated with moderate phenotype in XP group A Moroccan families; this result will also contribute to improve the molecular diagnosis of XP disease in Moroccan patients.
Mutations in the
gene are usually associated with recessive inherited diseases including Zellweger spectrum disorders. In this work, we identified a new pathogenic missense homozygous
mutation ...(p.Leu1026Pro, c.3077T>C) in two Moroccan syndromic deaf siblings from consanguineous parents. This variation is located in the P-loop containing nucleoside triphosphate hydrolase of protein domain and probably causes an alteration in the hydrolysis of ATP.
One of the most prevalent sensorineural disorders, autosomal recessive non-syndromic hearing loss (ARNSHL) which can affect all age groups, from the newborn (congenital) to the elderly (presbycusis). ...Important etiologic, phenotypic, and genotypic factors can cause deafness. So far, the high genetic variability that explains deafness makes molecular diagnosis challenging. In Morocco, the
GJB2
gene is the primary cause of non-syndromic hereditary deafness, while the existence of a variant in the
LRTOMT
gene is the second cause of this condition. After excluding these two frequently occurring
GJB2
and
LRTOMT
variants, whole-exome sequencing was carried out in two Moroccan consanguineous families with hearing loss. As a result, two novel variants in the
TMPRSS3
(c.1078G>A, p. Ala 360Thr) and
FOXI1
(c.6C>G, p. Ser 2Arg) genes have been discovered in deaf patients and the pathogenic effect has been anticipated by several bioinformatics and molecular modeling systems. For the first time, these variants are identified in the Moroccan population, showing the population heterogeneity and demonstrating the value of the WES in hearing loss diagnosis.
Autosomal recessive non-syndromic hearing loss (ARNSHL) is one of the most common genetic diseases in human and is subject to important genetic heterogeneity, rendering molecular diagnosis difficult. ...Whole-exome sequencing is thus a powerful strategy for this purpose. After excluding GJB2 mutation and other common mutations associated with hearing loss in Morocco, whole-exome sequencing was performed to study the genetic causes of one sibling with ARSHNL in a consanguineous Moroccan family. After filtering data and Sanger sequencing validation, one novel pathogenic homozygous mutation c.1810C>G (p.Arg604Gly) was identified in TMC1, a gene reported to cause deafness in various populations. Thus, we identified here the first mutation in the TMC1 gene in the Moroccan population causing non-syndromic hearing loss.
•Sensorineural hearing loss is the most prevalent human genetic sensory defect.•A novel TMC1 gene mutation is described.•Whole exome sequencing was suitable for identifying mutation in the proband.•TMC1 can be a contributor of hearing loss in the Moroccan population.
In the present work, we identified two novel compound heterozygote mutations in the
GPR98
(G protein-coupled receptor 98) gene causing Usher syndrome. Whole-exome sequencing was performed to study ...the genetic causes of Usher syndrome in a Moroccan family with three affected siblings. We identify two novel compound heterozygote mutations (c.1054C > A, c.16544delT) in the
GPR98
gene in the three affected siblings carrying post-linguale bilateral moderate hearing loss with normal vestibular functions and before installing visual disturbances. This is the first time that mutations in the
GPR98
gene are described in the Moroccan deaf patients.
Mutations in the mesenchymal epithelial transition factor (MET) gene are frequently associated with multiple human cancers but can also lead to human non-syndromic autosomal recessive deafness ...(DFNB97). In the present study, we identified a novel homozygous missense mutation in the MET gene causing a non-syndromic hearing impairment DFNB97 form. Whole-exome sequencing was performed to determine the genetic causes of hearing loss in a Moroccan consanguineous family with an affected daughter. The structural analysis of native and mutant in the SEMA domain of the MET receptor was investigated using a molecular dynamics simulation (MDS) approach. We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment. The results of the MDS approach show that an Ile316Met mutation in the SEMA domain leads to protein flexibility loss. This may produce a major impact on the structural conformation of the MET receptor, which also affects the function and binding site of the receptor. This is the first time that a mutation in the MET gene is described in a Moroccan family. Moreover, this study reports the second family in the world associating deafness and mutation in the MET gene.
ABSTRACT
The Mediterranean basin has been the theater of migration crossroads followed by settlement of several societies and cultures in prehistoric and historical times, with important consequences ...on genetic and genomic determinisms. Here, we present the Mediterranean Founder Mutation Database (MFMD), established to offer web‐based access to founder mutation information in the Mediterranean population. Mutation data were collected from the literature and other online resources and systematically reviewed and assembled into this database. The information provided for each founder mutation includes DNA change, amino‐acid change, mutation type and mutation effect, as well as mutation frequency and coalescence time when available. Currently, the database contains 383 founder mutations found in 210 genes related to 219 diseases. We believe that MFMD will help scientists and physicians to design more rapid and less expensive genetic diagnostic tests. Moreover, the coalescence time of founder mutations gives an overview about the migration history of the Mediterranean population. MFMD can be publicly accessed from http://mfmd.pasteur.ma.
Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural ...hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness.
After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes.
Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A, both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively.
We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes.
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