Related Experiment Video

Updated: Sep 5, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

Potentially Deleterious Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in the Human MCPH1 Gene: Systematic In

Rizwana Kousar¹, Sadia Latif¹, Mohammed Turki Hussain Alharthi²

¹Department of Biology, Allama Iqbal Open University, Islamabad, Pakistan, aiou.edu.pk.

|September 4, 2026

Abstract

Background:

The microcephalin 1/BRITI1 (MCPH1) gene has been implicated in microcephaly (MCPH), primary ciliary dyskinesia (PCD) syndrome, enlarged cranial volume, and pancreatic and breast cancers. It functions as a tumor suppressor and shows reduced expression in various cancer types. Therefore, the identification of MCPH1 polymorphisms is of paramount importance.

Aims And Objectives:

Considering the multifaceted role of MCPH1, this study is aimed at examining the structural and functional impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on MCPH1 using in silico tools to understand its potential role in pathogenesis.

Methodology:

In the present investigation, a wide array of in silico tools was deployed to explicate putative pathogenic missense/nsSNPs that might impact the structural integrity and molecular functions of MCPH1. The mining of damaging nsSNPs was carried out based on the evolutionary conservation of sequence information, prediction of protein stability, interaction analysis, and their potential impact was assessed using structure prediction and 3D modeling, and interaction with other genes/pathways.

Results:

In the initial screening, SIFT, PolyPhen-2, SNAP2, Align GVGD, PhD-SNP, PANTHER, and SNPs&GO revealed 23 potential deleterious SNPs in MCPH1. Population frequency analysis using gnomAD revealed that the prioritized variants were extremely rare in the global population. I-mutant and ConSurf further revealed that 16 nsSNPs exhibited a decrease in protein stability due to changes in size and charge. I-TASSER was used to predict wild-type and mutant protein 3D structures. The potential effect of variation on 3D protein structure was assessed using the Chimera tool, which presented the probable structural loss in eight variants, including p.A11D, p.H49D, p.T59I, p.W60S, p.W60C, p.L74P, p.C79G, and p.L781P. Most of these potential variants resided in the N-terminal BRCT domain, which is implicated in neurodevelopment, and thus may lead to the pathogenesis of primary microcephaly. Furthermore, single-cell transcriptomic mapping of MCPH1 against dataset of 33,206 cells from malformations of cortical development detected MCPH1 expression across multiple cellular populations. This broad distribution suggested potential MCPH1 function across several neural and glial cell populations.

Conclusion:

The potentially deleterious nsSNPs predicted in this study can be of great significance in understanding MCPH1-related diseases and may serve as potential targets for future functional validation and therapeutic interventions.

Keywords:

MCPH MCPH1 in silico tools nsSNPs

More Related Videos

In Vivo Modeling of the Morbid Human Genome using Danio rerio

In Vivo Modeling of the Morbid Human Genome using Danio rerio

Published on: August 24, 2013

Related Concept Videos

Nonsense-mediated mRNA Decay

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...

Single Nucleotide Polymorphisms-SNPs

Single Nucleotide Polymorphisms-SNPs

A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...

Mutations

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously during DNA replication or be induced by environmental factors. Mutations can be characterized in several ways: by whether and how they alter the amino acid sequence of the protein, by the scale of the DNA affected, and by whether they affect somatic or germline cells.Consequences of Point Mutations at the Molecular LevelMutations that affect a single nucleotide are called point mutations. When point mutations...

Comparing Copy Number Variations and SNPs

Comparing Copy Number Variations and SNPs

Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...

Mismatch Repair

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...

Signal Sequences and Sorting Receptors

Signal Sequences and Sorting Receptors

Signal sequences are short amino acid sequences that guide newly synthesized proteins to their proper location within the cell. Classical signal sequences are fifteen to sixty amino acids long and present at the N-terminus of a polypeptide chain. Each signal sequence has a conserved segment of basic residues towards their N terminus, a hydrophobic core, and a C-terminus rich in polar residues. The C-terminus also contains a signal cleavage site and features a -3 -1 sequence motif. The -3-1...

Articles linked to this work by shared authors, journal, and citation graph.

Design, synthesis, and biological evaluation of a new series of amide-linked chalcone derivatives as selective COX-2 inhibitors.

RSC advances·2026

Molecular Profiling of Soil-Derived Bacillus subtilis and Bacillus paralicheniformis: Evaluation of Anticancer and Antibacterial Efficacy Against Gastrointestinal Pathogens.

Current issues in molecular biology·2026

Iodine-catalyzed green and efficient synthesis of secondary and tert-esters of N-acetyl-protected amino acids.

RSC advances·2026

Design, synthesis, and enzyme kinetic evaluation of oxadiazole derivatives as nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors: an integrated in vitro and in silico approach.

RSC advances·2026

A novel protein truncating mutation of TTC8 causes Bardet-Biedl Syndrome (BBS) in a Pakistani family.

Genetics and molecular biology·2026

Design, synthesis, and biological evaluation of novel chalcone derivatives: integrating molecular docking with in vivo anti-inflammatory and antinociceptive studies.

RSC advances·2026

See all related articles