Rare neurological manifestations in a Saudi Arabian patient with Ehlers-Danlos syndrome and a novel homozygous variant in the TNXB gene.

We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.

Loss-of-Function Mutations in KIF15 Underlying a Braddock-Carey Genocopy.

Braddock-Carey Syndrome (BCS) is characterized by microcephaly, congenital thrombocytopenia, Pierre-Robin sequence (PRS), and agenesis of the corpus callosum. BCS has been shown to be caused by a 21q22.11 microdeletion that encompasses multiple genes. Here, we report a BCS genocopy characterized by congenital thrombocytopenia and PRS that is caused by a loss-of-function mutation in KIF15 in a consanguineous Saudi Arabian family. Mutations of mitotic kinesins are a well-established cause of microcephaly. To our knowledge, KIF15 is the first kinesin to be associated with congenital thrombocytopenia.

Saudi Arabian CML patient with a novel four-way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).

BACKGROUND: The vast majority of chronic myeloid leukemia (CML) patients have a single translocation t(9;22)(q34;q11), BCR/ABL1 fusion genes, which is regarded as the hallmark of CML. However, around 5 to 10% of CML patients exhibit the involvement of a third chromosome. In some very rare cases a fourth or even fifth chromosome can be involved with the t(9;22). METHODS: This case report is based on a 40-year-old Saudi Arabian male patient, diagnosed with CML in lymphoid blast crisis, and observed to have a four-way 46 XY, t(9;22;5;2)(q34;q11.2;p13;q44) translocation. The BCR/ABL1 fusion was identified by fluorescent in situ hybridization (FISH). Additionally, the BCR/ABL1 p210 mRNA fusion transcripts were identified by a molecular test. RESULTS: The clinical and prognostic impact of additional partner chromosomes to t(9;22) remains unknown. The CML patient with this novel four-way translocation t(9;22;5;2) progressed to blast crisis and was resistant to Tyrosine Kinase Inhibitor (TKI) therapy. Therefore, this case is more in alignment with the negative impact of additional partner chromosomes to the translocation at t(9;22). CONCLUSION: Here we report for the first time a novel four-way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).

Novel MFN2 Missense Mutation Induces Hereditary Axonal Motor and Sensory Neuropathy in a Saudi Arabian Family.

Hereditary axonal motor and sensory neuropathy or Charcot-Marie-Tooth type 2 (CMT2) is a common inherited peripheral neuropathy. Major symptomatologic signs vary from minimal to significant weakness and loss of sensation, feet usually affected more than hands. It may also cause visual acuity impairment, hearing loss, and skeletal deformity. CMT2 classification is based on the clinical, electrophysiological, and genetic inheritance pattern. Dominant CMT2 is classified from CMT2A to CMT2N and recessive CMT2 into CMT2B1 and CMT2B2. CMT2A is the most frequent subtype of CMT2 and caused by mutations in the mitofusin 2 (MFN2) gene. We hereby report a Saudi Arabian CMT2A patient with a variant c.58C>T of the MFN2 gene mutation.

[Dominant negative activity of mutated p53 proteins]. / Activité dominante négative des protéines p53 mutées.

Tumor suppressor gene inactivation as proposed by the Knudson model implies a sequential inactivation of two alleles of a gene. For example, the first allele is inactivated by a missense mutation, and the second one is inactivated by a deletion or insertion. The alteration of the p53 tumor suppressor gene is far to correspond only to this model. In the great majority of cancers, the mutated allele of p53 coexists with the normal allele. It is well known that the transcriptional activity is one of the most important functions of p53. The p53 protein is active as a tetramer (this complex activates the expression of targeted genes by binding to its consensus DNA sequence called the p53 response element). Experimental evidence shows that wild-type p53 interacts with mutant proteins to form heterotetramers. In association with wild-type proteins, mutant proteins drive the wild-type subunits into a mutant conformation. This association leads to a loss of trans-activating function. The capacity of mutant subunits to form heterotetramers with wild-type subunits and to commit them into a mutant conformation is called << dominant negative effect >>. Many p53 mutant proteins possess this dominant negative activity. Recently, several factors, which are implicated in the control of the dominant negative activity of p53 mutants, have been identified. The elucidation of these complex molecular functions, which are implicated in the dominant negative activity of the p53 mutated protein represents an important aspect in the comprehension of the biological mechanisms involved in carcinogenesis.

Novel Homozygous Missense Mutation in CAPN3 Gene Detected in a Saudi Arabian Family With Limb-Girdle Muscular Dystrophy Type 2A.

More than 300 mutations were identified in Calpainopathy (CAPN3) gene in limb-girdle muscular dystrophy type 2A (LGMD2A) patients. LGMD2A type is also known as Calpainopathy, which is characterized by selective atrophy and weakness of proximal limb muscles. We report a Saudi Arabian family with weakness in limb-girdle distribution: waddling gait, positive Gowers' sign, and marked muscle atrophy in the shoulder and pelvic girdle muscles. We sequenced all exonic and intronic regions of the CAPN3 gene and identified c.1699 G>A variant as a novel variant not previously described in other patients. In silico predictions indicate that this is probably a disease-causing mutation. Here, for the first time, we report this c.1699 G>A new variant in the CAPN3 gene that can be considered as a robust genetics factor causing LGMD2A disease.

First report of surra (Trypanosoma evansi infection) in a Tunisian dog.

Trypanosoma evansi, the agent of surra, is a salivarian trypanosome, originating from Africa. Surra is a major disease in camels, equines and dogs, in which it can often be fatal in the absence of treatment. Animals exhibit nonspecific clinical signs (anaemia, loss of weight and abortion). In the present survey, a blood sample was collected in Sousse (Central Tunisia) from a dog that presented clinical signs of trypanosomiasis. Giemsa-stained blood smears and PCR were performed. ITS1 sequences from blood had 99.8 and 99.5% homology with published T. evansi sequences from cattle and camels, respectively. To our knowledge, this is the first report of T. evansi in a Tunisian dog.

The dominant-negative effect of p53 mutants and p21 induction in tetraploid G1 arrest depends on the type of p53 mutation and the nature of the stimulus.

Many p53 mutant proteins possess a dominant-negative activity that is under the control of several factors, namely p53 mutations and the cell type. The goals of our study were to determine the following: (1) the dominant-negative effect of different p53 mutations in response to mitotic spindle inhibitors, and (2) if this dominant-negative activity is dependent on the nature of the stimulus. We therefore examined the cellular response of the near-diploid LoVo colon carcinoma cell line possessing two wild-type TP53 alleles and three other clones transfected with different TP53 mutants (p53-273H, p53-175H, and p53-143A) to treatments with different mitotic spindle inhibitors. Flow cytometric studies and analysis of retinoblastoma protein (pRb) dephosphorylation and 5-bromo-2'-deoxyuridine incorporation by immunocytochemistry revealed a tetraploid G1 arrest of the wild-type LoVo clone and the p53-273H mutant clone after exposure to mitotic spindle inhibitors, preventing tetraploid cells from entering into an additional S phase. On the other hand, the p53-175H and p53-143A mutant clones re-enter S phase with no apparent arrest. Therefore, our results confirm that p53 mutant dominant-negative activity and the tetraploid G1 arrest in response to mitotic spindle inhibitor treatment depend on the type of p53 mutation, involve p21 induction, and require pRb dephosphorylation. Moreover, when we compare our results with those obtained by other investigators after ionizing radiation exposure using the same cell lines, we identify the nature of the stimulus as a new factor that determines the dominant-negative effect of p53 mutants.

Hyalomma scupense (Acari, Ixodidae) in northeast Tunisia: seasonal population dynamics of nymphs and adults on field cattle.

Hyalomma scupense is a two-host tick infesting mainly cattle representing in North Africa the vector of tropical theileriosis (Theileria annulata infection), a major tick-borne disease affecting cattle. Any effective control programme of ticks requires a good knowledge of the biology of the target species. In the present study, three cattle farms in northeast Tunisia were surveyed during the activity seasons for adult and nymphs of Hyalomma scupense. Several indicators were studied, including chronological indicators, infestation prevalence, infestation intensity and feeding predilection sites of the ticks. The adult ticks were present from mid-June to late November. Nymphs were observed on animals from early September to late November. A large proportion of the ticks were attached in the posterior udder quarters: 41% and 64% of adult ticks and nymphs, respectively. The animals that were heavily infested by adult ticks were also heavily infested by nymphs. Moreover, 17% of adult ticks and 53% of nymphs were present on only 5% of cattle population. These data are important for the success of targeted acaricide application leading to a dramatic decrease of acaricide quantity needed for the treatment. When the preferential sites of attachment are known, the effectiveness of manual removal of ticks can be improved. The presence of highly infested animals is to be considered when any control programme is implemented, since these animals harbour a high proportion of the ticks.