scholarly journals Homozygous mutation in MCM7 causes autosomal recessive primary microcephaly and intellectual disability

2021 ◽  
pp. jmedgenet-2020-107518
Author(s):  
Ethiraj Ravindran ◽  
Cynthia Gutierrez de Velazco ◽  
Ali Ghazanfar ◽  
Nadine Kraemer ◽  
Abdul Waheed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intellectual Disability ◽  
Expression Pattern ◽  
Autosomal Recessive ◽  
Dna Helicase ◽  
Primary Microcephaly ◽  
Neurodevelopmental Disease ◽  
Severe Intellectual Disability ◽  
Mcm Complex ◽  
Autosomal Recessive Primary Microcephaly

BackgroundMinichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity and is thereby important for the initiation and elongation of the replication fork and highly expressed in proliferating neural stem cells.MethodsWhole-exome sequencing was applied to identify the genetic cause underlying the neurodevelopmental disease of the index family. The expression pattern of Mcm7 was characterised by performing quantitative real-time PCR, in situ hybridisation and immunostaining. To prove the disease-causative nature of identified MCM7, a proof-of-principle experiment was performed.ResultsWe reported that the homozygous missense variant c.793G>A/p.A265T (g.7:99695841C>T, NM_005916.4) in MCM7 was associated with autosomal recessive primary microcephaly (MCPH), severe intellectual disability and behavioural abnormalities in a consanguineous pedigree with three affected individuals. We found concordance between the spatiotemporal expression pattern of Mcm7 in mice and a proliferative state: Mcm7 expression was higher in early mouse developmental stages and in proliferative zones of the brain. Accordingly, Mcm7/MCM7 levels were detectable particularly in undifferentiated mouse embryonal stem cells and human induced pluripotent stem cells compared with differentiated neurons. We further demonstrate that the downregulation of Mcm7 in mouse neuroblastoma cells reduces cell viability and proliferation, and, as a proof-of-concept, that this is counterbalanced by the overexpression of wild-type but not mutant MCM7.ConclusionWe report mutations of MCM7 as a novel cause of autosomal recessive MCPH and intellectual disability and highlight the crucial function of MCM7 in nervous system development.

Autosomal Recessive Primary Microcephaly (MCPH): An Update

2017 ◽  
Vol 48 (03) ◽  
pp. 135-142 ◽  
Author(s):  
Deborah Morris-Rosendahl ◽  
Angela Kaindl ◽  
Sami Zaqout
Keyword(s):  
Intellectual Disability ◽  
Head Circumference ◽  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Speech Disorder ◽  
Rare Disorder ◽  
Primary Microcephaly ◽  
Expressive Speech ◽  
Autosomal Recessive Primary Microcephaly

AbstractAutosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.

scholarly journals A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family

2014 ◽  
Vol 23 (22) ◽  
pp. 5940-5949 ◽  
Author(s):  
Muzammil A. Khan ◽  
Verena M. Rupp ◽  
Meritxell Orpinell ◽  
Muhammad S. Hussain ◽  
Janine Altmüller ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Autosomal Recessive ◽  
Pakistani Family ◽  
Primary Microcephaly ◽  
Autosomal Recessive Primary Microcephaly

Mutation Analysis of the ASPM Gene in 18 Pakistani Families With Autosomal Recessive Primary Microcephaly

2009 ◽  
Vol 25 (6) ◽  
pp. 715-720 ◽  
Author(s):  
Rizwana Kousar ◽  
Hira Nawaz ◽  
Maryam Khurshid ◽  
Ghazanfer Ali ◽  
Saad Ullah Khan ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Autosomal Recessive ◽  
Primary Microcephaly ◽  
Autosomal Recessive Primary Microcephaly ◽  
Pakistani Families

Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene

Neurogenetics ◽  
2006 ◽  
Vol 7 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Asma Gul ◽  
Muhammad Jawad Hassan ◽  
Saqib Mahmood ◽  
Wenje Chen ◽  
Safa Rahmani ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Sequence Variants ◽  
Primary Microcephaly ◽  
Genetic Studies ◽  
Autosomal Recessive Primary Microcephaly ◽  
Pakistani Families

scholarly journals Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2163
Author(s):  
Desaraju Suresh Bhargav ◽  
N. Sreedevi ◽  
N. Swapna ◽  
Soumya Vivek ◽  
Srinivas Kovvali
Keyword(s):  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Frameshift Mutation ◽  
Protein Gene ◽  
Single Gene ◽  
Primary Microcephaly ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
The Family ◽  
Autosomal Recessive Primary Microcephaly

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly.  Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

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.

A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report

2020 ◽  
Author(s):  
Afsaneh BAZGIR ◽  
Mehdi AGHA GHOLIZADEH ◽  
Faezeh SARVAR ◽  
Zahra PAKZAD
Keyword(s):  
Intellectual Disability ◽  
Frameshift Mutation ◽  
Genetic Disorder ◽  
Normal Function ◽  
Molecular Testing ◽  
Homozygous Mutation ◽  
Primary Microcephaly ◽  
Iranian Patient ◽  
Whole Exome ◽  
Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.

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