Two New Cases of Primary Microcephaly with Neuronal Migration Defect Caused by Truncating Mutations in the ASPM Gene

2021 ◽  
pp. 1-8
Author(s):  
Ayberk Türkyılmaz ◽  
Safiye Gunes Sager
Keyword(s):  
Gray Matter Volume ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Primary Microcephaly ◽  
Congenital Deficiency ◽  
Basic Characteristics ◽  
Neuronal Migration Defect ◽  
Spindle Function ◽  
Related Proteins ◽  
Truncated Variants

Autosomal recessive primary microcephaly (MCPH) is a uncommon disorder due to congenital deficiency in the development of the cerebral cortex, characterized by a head circumference below 2 SD. MCPH is a group of diseases with genetic heterogeneity and has been reported by the Online Mendelian Inheritance In Man® (OMIM) database and associated with 25 different genes. It is known that MCPH cases are most frequently associated with abnormal spindle-like, microcephaly-associated (<i>ASPM</i>) gene mutations. The ASPM protein consists of an N-terminal 81 IQ (isoleucine-glutamine) domain, a calponin-homology domain, and a C-terminal domain. It interacts with calmodulin and calmodulin-related proteins via the IQ domain and acts as a part in mitotic spindle function. The basic characteristics of cases with <i>ASPM</i> gene mutations are microcephaly (below <b>−</b>3 SD) present before 1 year of age, intellectual disability, and the absence of other congenital anomalies. Macroscopic organization of the brain is preserved in cases with <i>ASPM</i> mutation, and a decrease in brain volume, particularly gray matter volume loss and a simplified gyral pattern are observed. Cortical migration defects are a very rare finding in patients with <i>ASPM</i> mutations. In the present study, we aimed to discuss the clinical and genetic findings in 2 cases with cortical dysplasia in which truncated variants in the <i>ASPM</i> gene were detected, particularly in terms of genotype-phenotype correlation in comparison with the literature.

scholarly journals Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Cao ◽  
Ruixue Zhang ◽  
Liang Yong ◽  
Shirui Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Molecular Genetic ◽  
Family Members ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Chinese Family ◽  
Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

Natural History of 33 Patients with Upshaw-Schulman Syndrome Has Revealed That All the Gravida Develop Thrombocytopenia, Often Followed by Thrombotic Microangiopathy with Stillbirth.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3211-3211
Author(s):  
Yoshihiro Fujimura ◽  
Masanori Matsumoto ◽  
Koichi Kokame ◽  
Hideo Yagi ◽  
Ayami Isonishi ◽  
...  
Keyword(s):  
Natural History ◽  
Late Onset ◽  
Gene Mutations ◽  
Fresh Frozen Plasma ◽  
Hemorrhagic Disease ◽  
Onset Type ◽  
Congenital Deficiency ◽  
Fresh Frozen ◽  
Von Willebrand

Abstract Upshaw-Schulman syndrome (USS) is a congenital deficiency of the activity of von Willebrand factor (VWF)-cleaving protease or ADAMTS13 due to its gene mutations. USS is a complex thrombo-hemorrhagic disease, but its hallmark is severe neonatal jaundice soon after birth that often requires for exchange blood transfusion, and subsequently during childhood they have repeated episodes of chronic thrombocytopenia and hemolytic anemia that are reversed by infusions of fresh frozen plasma. However, after a discovery of ADAMTS13, the presence of two phenotype expression on USS-patients was described; one is the early-onset type as abovementioned, and the other is the late-onset type which is asymptomatic during childhood and the first bout develops after adolescent or during adulthood, in association with infections or pregnancy. During the past 8 years, we diagnosed 33 patients with USS. Through analyzing the natural history and the phenotype-genotype expression in these patients, and more specifically to 9 USS-patients who had their first bout at pregnancy, we found that two clinical phenotypes of USS are mostly attributable to misdiagnosis or overlook of thrombocytopenia during childhood, and excluded a possibility of the concern on a trace amount of ADAMTS13 activity which has not been evaluated by the previous methods. Further, in vitro studies we have clearly shown that platelet aggregation or thrombi formation under high shear stress is tremendously up-regulated in the absence of ADAMTS13, that occurs proportionally to the amount of high VWF multimers, that in part is assumed to be an in vitro reflection of the circulation in USS-gravida. Figure Figure

scholarly journals CDK5RAP2 Is a Pericentriolar Protein That Functions in Centrosomal Attachment of the γ-Tubulin Ring Complex

2008 ◽  
Vol 19 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Ka-Wing Fong ◽  
Yuk-Kwan Choi ◽  
Jerome B. Rattner ◽  
Robert Z. Qi
Keyword(s):  
Autosomal Recessive ◽  
Macromolecular Complex ◽  
Mitotic Spindles ◽  
Microtubule Nucleation ◽  
Primary Microcephaly ◽  
Conserved Sequence ◽  
Ring Complex ◽  
Pericentriolar Material ◽  
Related Proteins ◽  
Autosomal Recessive Primary Microcephaly

Microtubule nucleation and organization by the centrosome require γ-tubulin, a protein that exists in a macromolecular complex called the γ-tubulin ring complex (γTuRC). We report characterization of CDK5RAP2, a novel centrosomal protein whose mutations have been linked to autosomal recessive primary microcephaly. In somatic cells, CDK5RAP2 localizes throughout the pericentriolar material in all stages of the cell cycle. When overexpressed, CDK5RAP2 assembled a subset of centrosomal proteins including γ-tubulin onto the centrosomes or under the microtubule-disrupting conditions into microtubule-nucleating clusters in the cytoplasm. CDK5RAP2 associates with the γTuRC via a short conserved sequence present in several related proteins found in a range of organisms from fungi to mammals. The binding of CDK5RAP2 is required for γTuRC attachment to the centrosome but not for γTuRC assembly. Perturbing CDK5RAP2 function delocalized γ-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in γTuRC attachment and therefore in the microtubule organizing function of the centrosome. Our findings suggest that centrosome malfunction due to the CDK5RAP2 mutations may underlie autosomal recessive primary microcephaly.

The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals

2014 ◽  
Vol 392 (1-2) ◽  
pp. 145-152 ◽  
Author(s):  
Hongsai Chen ◽  
Xiaoman Zhang ◽  
Zhihua Zhang ◽  
Tao Yang ◽  
Zhaoyan Wang ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Vestibular Schwannomas ◽  
Pathogenesis Related Proteins ◽  
Nf2 Gene ◽  
Pathogenesis Related ◽  
Related Proteins

scholarly journals Genetic classification and confirmation of inherited platelet disorders: current status in Korea

2020 ◽  
Vol 63 (3) ◽  
pp. 79-87 ◽  
Author(s):  
Ye Jee Shim
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Gene Mutations ◽  
Hematologic Malignancies ◽  
Mendelian Inheritance ◽  
Current Status ◽  
Genetic Classification ◽  
Granule Formation ◽  
Primary Hemostasis ◽  
Platelet Disorders

Inherited platelet disorders (IPDs), which manifest as primary hemostasis defects, often underlie abnormal bleeding and a family history of thrombocytopenia, bone marrow failure, hematologic malignancies, undefined mucocutaneous bleeding disorder, or congenital bony defects. Wide heterogeneity in IPD types with regard to the presence or absence of thrombocytopenia, platelet dysfunction, bone marrow failure, and dysmegakaryopoiesis is observed in patients. The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes involved in various platelet biogenesis steps have been implicated in IPDs. Representative IPDs resulting from defects in specific pathways, such as thrombopoietin/MPL signaling; transcriptional regulation; granule formation, trafficking, and secretion; proplatelet formation; cytoskeleton regulation; and transmembrane glycoprotein signaling are reviewed, and the underlying gene mutations are discussed based on the National Center for Biotechnology Information database and Online Mendelian Inheritance in Man accession number. Further, the status and prevalence of genetically confirmed IPDs in Korea are explored based on searches of the PubMed and KoreaMed databases. IPDs are congenital bleeding disorders that can be dangerous due to unexpected bleeding and require genetic counseling for family members and descendants. Therefore, the pediatrician should be suspicious and aware of IPDs and perform the appropriate tests if the patient has unexpected bleeding. However, all IPDs are extremely rare; thus, the domestic incidences of IPDs are unclear and their diagnosis is difficult. Diagnostic confirmation or differential diagnoses of IPDs are challenging, time-consuming, and expensive, and patients are frequently misdiagnosed. Comprehensive molecular characterization and classification of these disorders should enable accurate and precise diagnosis and facilitate improved patient management.

Diverse Functional Implications of ADAMTS13 Gene Mutations in Patients with TTP and Congenital Deficiency.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 513-513 ◽  
Author(s):  
Roberta Donadelli ◽  
Federica Banterla ◽  
Cristina Capoferri ◽  
Miriam Galbusera ◽  
Zaverio M. Ruggeri ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Proteolytic Activity ◽  
Signal Sequence ◽  
Gene Mutations ◽  
Kinetic Studies ◽  
Missense Mutations ◽  
Wild Type ◽  
Small Vessels ◽  
Congenital Deficiency ◽  
Reported Data

Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the VWF cleaving protease ADAMTS13, causing life-threatening disseminated microvascular thrombosis. Here we report four missense mutations (V88M, G1239V, R1219W, R1123C) in three patients with congenital ADAMTS13 deficiency. The three subjects carrying the mutations had less than 10% normal ADAMTS13 plasma antigen levels (measured by ELISA), which is consistent with previously reported data showing that most ADAMTS13 mutations in TTP patients result in impaired secretion of the protein. To evaluate whether the small amount of the mutant protease present in patients’ plasma had proteolytic activity, we cloned the ADAMTS13 cDNA in the pMT/Bip/His Drosophila expression vector and introduced the respective mutations by directed mutagenesis technique using wild-type cDNA as a template. These wild-type and mutant constructs were stably transfected into S2 Drosophila cells under the influence of the Drosophila BiP protein signal sequence, which allows the protein to be secreted into the medium and overcomes impaired secretion caused by the mutations. The induction of the histidine-tagged ADAMTS13 recombinants following the addition of copper was analyzed by Western blotting using an anti-hexahistidine monoclonal antibody. Equal amounts of recombinant ADAMTS13 proteins were used to evaluate proteolytic activity of recombinant proteins by cleavage of the rVWF A1-A2-A3 substrate. The proteolytic carboxyl terminal product of about 30 kDa was visualized by Western blot with a mouse monoclonal antibody directed against an epitope contained within the A3 domain of VWF. All the four missense mutations exhibited reduced activity: V88M:40%, G1239V: 66%, R1219W: 62% and R1123C: 64% of wild type activity . The results were also confirmed by collagen binding assay. For the the V88M mutation (located in the metalloprotease domain), decreased activity was confirmed by kinetic studies. In conclusion, mutant ADAMTS13 proteins found in patients with TTP, besides defective secretion, also have reduced protease activity. The mechanisms of the deficiency will be the matter of further studies.

Absence of microcephalin gene mutations in a large cohort of non-consanguineous patients with autosomal recessive primary microcephaly

2010 ◽  
Vol 152A (11) ◽  
pp. 2882-2885 ◽  
Author(s):  
Iris Scala ◽  
Luigi Titomanlio ◽  
Ennio Del Giudice ◽  
Sandrine Passemard ◽  
Chiara Figliuolo ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Gene Mutations ◽  
Large Cohort ◽  
Primary Microcephaly ◽  
Autosomal Recessive Primary Microcephaly

scholarly journals Novel Roles for Saccharomyces cerevisiae Mitotic Spindle Motors

1999 ◽  
Vol 147 (2) ◽  
pp. 335-350 ◽  
Author(s):  
Frank R. Cottingham ◽  
Larisa Gheber ◽  
Dana L. Miller ◽  
M. Andrew Hoyt
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitotic Spindle ◽  
Structural Integrity ◽  
Cytoplasmic Dynein ◽  
Spindle Positioning ◽  
Bipolar Spindle ◽  
Accessory Factor ◽  
Spindle Function ◽  
Related Proteins ◽  
Spindle Structure

The single cytoplasmic dynein and five of the six kinesin-related proteins encoded by Saccharomyces cerevisiae participate in mitotic spindle function. Some of the motors operate within the nucleus to assemble and elongate the bipolar spindle. Others operate on the cytoplasmic microtubules to effect spindle and nuclear positioning within the cell. This study reveals that kinesin-related Kar3p and Kip3p are unique in that they perform roles both inside and outside the nucleus. Kar3p, like Kip3p, was found to be required for spindle positioning in the absence of dynein. The spindle positioning role of Kar3p is performed in concert with the Cik1p accessory factor, but not the homologous Vik1p. Kar3p and Kip3p were also found to overlap for a function essential for the structural integrity of the bipolar spindle. The cytoplasmic and nuclear roles of both these motors could be partially substituted for by the microtubule-destabilizing agent benomyl, suggesting that these motors perform an essential microtubule-destabilizing function. In addition, we found that yeast cell viability could be supported by as few as two microtubule-based motors: the BimC-type kinesin Cin8p, required for spindle structure, paired with either Kar3p or Kip3p, required for both spindle structure and positioning.

Screening for ADAMTS13 Gene Mutations in Thrombotic Thrombocytopenic Purpura Reveals a New Deletional Mutation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2300-2300
Author(s):  
Teresa Fidalgo ◽  
Patricia Martinho ◽  
Ramon Salvado ◽  
Catarina Silva Pinto ◽  
Dalila Marques ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Protein Identification ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Thrombocytopenic Purpura ◽  
Congenital Deficiency ◽  
Protein Clearance ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Thrombotic Thrombocytopenic Purpura (TTP) is a rare severe thrombotic microangiopathy due to the presence of ultra large von Willebrand factor (UL-vWF) multimers in circulation. The aetiology has been linked to a congenital deficiency or inhibition of the vWF-cleaving protease (ADAMTS-13) activity by autoantibodies, which neutralise the enzymatic activity or bind the protease, increasing the plasmatic clearance (non-neutralising). The presence of autoantibodies can be associated with mutations and polymorphisms (SNPs) in the ADAMTS-13 gene. The goal of this study was to characterize the ADAMTS-13 in 4 female patients with acute TTP episodes. The clinical picture was characterized by neurological symptoms and microangiopathic hemolytic anemia (Hb 6 – 9 g/dL), thrombocytopenia (platelets 4 – 47 x109/L), elevated LDH (1874 – 4922 IU/mL). In one patient TTP episodes occurred during 4 pregnancies resulting in fetal deaths; one patient has systemic lupus. No precipitant factors were identified in the other 2 women; 1 of them had 3 TTP episodes. Methodology: ADAMTS-13 antigen and IgG anti-ADAMTS-13 were studied by ELISA (American Diagnostica). The vWF multimeric pattern was analyzed by SDS electroforesis, Western Blot, imunofixation and densitometry. Mutations screening along the 29 exons and boundaries of the ADAMTS-13 gene was performed by direct sequencing. Results: All the patients presented UL-vWF and autoantibodies anti-ADAMTS-13 and decreased ADAMTS-13 antigen. ADAMTS-13 gene studies identified SNPs in the four patients and mutations 764_776 del12 and R1096H, in heterozygosity, in the two patients with TTP associated with pregnancy and lupus, respectively. ADAMTS13 ADAMTS13 gene Patients Age TTP UL vWF Ag (ng/ml) IgG (AU/ml) Mutation Modulators SNPs Reference range: Ag: 485–1242 ng/ul; IgG: cutoff &gt;13.9 AU/ml; *3 episodes; **4 episodes I 73 idiopatic + &lt;62.5 18 (pos) No mut R7W (Htz); Q488E (Hm); II 41 Idiopatic* + 127 20.3 (pos) No mut R7W (Hm); Q488E (Hm)&#x2028; P618A (Hm); A732V (Hm) III 32 lupus + 284 30 (pos) E25, R1096H (Htz) R7W (Htz); Q488E (Hm) IV 26 Pregnancy** + &lt;62.5 22.6 (pos) E7, 764_776del12 (Htz) R625H (Hm) Discussion: PTT in these four patients was associated with antibodies anti-ADAMTS-13 and low levels of protein. Identification of the R7W and Q488E SNPs, described as positive modulators of protein secretion, on Patient I suggests the presence of the non-neutralising type of antibodies responsible for an increased plasmatic protein clearance. The positive modulation of the same SNPs on Patient II and III may be abolished by the presence of SNPs P618A and A732V (Camilleri et al; Pleimaueur et al) on Patient II and the mutation R1096H (Meyer et al) on Patient III. The not previously described mutation 764_776del12, identified on Patient IV, is likely to disturb the protein aminoacid composition, compromising the protease structure and function. This patient had a PTT episode in each of her four pregnancies.

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