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PubMed2026

A recurrent CCDC82 frameshift variant associated with syndromic neurodevelopmental disorder in a consanguineous Pakistani family.

BACKGROUND: Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. METHODS: Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. RESULTS: Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. CONCLUSIONS: This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.

Autosomal recessive↗
PubMed2026

Two iPSC lines with frameshift mutations in FTSJ1 as models for X-linked non-syndromic intellectual disability.

CRISPR/Cas9 was used to introduce two different FTSJ1 frameshift mutations into an existing human male iPSC line (UMGWi004-B). No additional genomic or chromosomal changes were detected. The modified iPSC express different stem cell markers and can be induced to differentiate into cells from all three germ layers. FTSJ1 is ubiquitously expressed and mutations in this X-chromosomal gene are involved in an intellectual developmental disorder (OMIM: #309549). These cells can be used to model the disease at the cellular and organoid level in their original state or after differentiation into cell types of interest.

Journal Article↗
PubMed1985

Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.

Certain mutant alleles at the low density lipoprotein (LDL) receptor locus produce receptors that bind LDL normally, but fail to cluster in coated pits and therefore cannot transport LDL into cells. We prepared genomic DNA libraries from cells of two individuals with this phenotype (internalization-defective familial hypercholesterolemia) and isolated the segment of the gene encoding the COOH-terminal cytoplasmic domain of the receptor. One mutant gene contains a single base substitution that changes a tryptophan codon (TGG) to a termination codon (TGA). This produces a receptor with only two amino acids in the cytoplasmic domain. The second mutant gene contains a four-base duplication, producing a frameshift that alters the reading frame. The cytoplasmic tail of this receptor has six of the normal amino acids plus eight additional amino acids. These data suggest that the signal for targeting the LDL receptor to coated pits resides in the cytoplasmic domain of the molecule.

Alleles↗
PubMedDate not supplied

Use of a new DNA intercalating fluorescing probe for studies on the mechanism of frameshift mutagenesis in Salmonella typhimurium.

As a general rule, ellipticine derivatives are mutagenic and intercalate into double-stranded nucleic acids. We have tested a new fluorescent ellipticine compound, 10[(1-carboxy-2-methylpropylidene)-amino]-9-hydroxy-2-methylell ipticinium (val-NMHE), for establishing the relationship between the amount of drug bound to nucleic acids in situ in Salmonella typhimurium and its biological effects: decrease of growth rate and mutagenesis. Val-NMHE is mutagenic only on Ames'strain TA 1977 which carries a + 1 frameshift mutation. On a per cell basis, the number of revertants is not linearly correlated to the amount of drug bound to nucleic acids: this number is relatively higher for increasing amounts of drug. This effect is not related to the mere probability of interaction between the drug molecule and its target, a GGGG/CCCC sequence. It might be explained by other hypotheses briefly discussed herein.

Alkaloids↗
PubMed1989

Abasic frameshift in DNA. Solution conformation determined by proton NMR and molecular mechanics calculations.

We have determined the three-dimensional structure of a non-self-complementary oligodeoxynucleotide duplex that contains a model abasic site. The duplex contains six GC base pairs plus the abasic site at the center of one strand and corresponds to an abasic frameshift. Two-dimensional NMR studies on the nonexchangeable protons show that the guanine bases on either side of the abasic site are stacked over each other and that the abasic site is rotated out of the helix. Close proton-proton interactions are observed between the H4' proton of the abasic site and sugar protons of the guanosine in the 5' direction, which allows the position of the free sugar to be well-defined. NOE buildup curves from NOESY spectra recorded at very short mixing times were used to calculate a set of interproton distances. This data set was incorporated into the refinement of the oligonucleotide structure by molecular mechanics calculations. Two conformations that differ in the sugar conformation of the guanosine next to the abasic site in the 3' direction were necessary to fit all the NMR data. One of these two conformations could only be stabilized by addition of counterions at specific sites.

Chemical Phenomena↗
PubMed2003

Detection of scalar couplings involving 2'-hydroxyl protons across hydrogen bonds in a frameshifting mRNA pseudoknot.

The -1 frameshift-stimulating mRNA pseudoknot from pea enation mosaic virus-1 (PEMV-1) is composed nearly entirely of RNA triple helix.(4) The 2'-OH hydroxyl protons of riboses C15 and C16 are hydrogen bond donors to the N1 atoms of adenosines A27 and A25, respectively, positioned in the minor groove of pseudoknot stem S1. In this paper, a nonrefocused (1)H,(15)N CPMG HSQC of uniformly (13)C,(15)N-labeled 33-mer PEMV-1 RNA has been tailored to reveal a correlation of the 2'-OH hydroxyl proton of C15 to the N1 nitrogen resonance of A27 mediated by a cross hydrogen bond scalar coupling. The (1h)J(2'OH,N) cross hydrogen bond scalar coupling constant determined from a quantitative 1D (15N) spin-echo difference experiment for the C15/A27 interaction is 1.7 +/- 0.1 Hz, while that for the C16/A25 interaction appears larger, 3.5 +/- 0.3 Hz, despite the fact that the corresponding direct correlation between the 2'-OH hydroxyl proton of C16 and the N1 of A25 is missing due to unfavorable solvent exchange properties. These findings reveal a detailed picture of critical noncanonical O-H.N hydrogen-bonding loop-stem interactions in an RNA triple helical structure.

Adenosine↗
PubMed1989

Phase variation in Bordetella pertussis by frameshift mutation in a gene for a novel two-component system.

Bordetella pertussis, the aetiological agent of whooping cough, coordinately regulates the expression of many virulence-associated determinants, including filamentous haemagglutinin, pertussis toxin, adenylyl cyclase toxin, dermonecrotic toxin and haemolysin. The coordinate regulation is apparent in the repression of synthesis of these determinants in response to environmental stimuli; a phenomenon known as antigenic or phenotypic modulation. B. pertussis also varies between metastable genetic states, or phases. There is a virulent phase in which virulence-associated determinants are synthesized, and an avirulent phase in which they are not. Previous studies have shown that a genetic locus, vir, is required for expression from many virulence-associated loci, and that replacing the cloned vir locus in trans can restore the virulent phase phenotype to spontaneously occurring avirulent phase strains. Here, we show that phase variation in one series of strains is due to a frameshift mutation within an open reading frame that is predicted to code for a Vir protein product. The deduced protein sequence is similar to both components of the 'two-component' regulatory system which control gene expression in response to environmental stimuli in a range of bacterial species.

Base Sequence↗
PubMed2003

Complexes between the nonsense-mediated mRNA decay pathway factor human upf1 (up-frameshift protein 1) and essential nonsense-mediated mRNA decay factors in HeLa cells.

mRNAs harbouring premature translation-termination codons are usually degraded by the nonsense-mediated mRNA decay (NMD) pathway. Human up-frameshift protein 1 (Hupf1) is an NMD factor that is conserved between yeast and mammals. To isolate cellular complexes that are formed with Hupf1 and to explore the role of cellular proteins in NMD, we generated a HeLa cell line that stably expresses Hupf1 bearing a double-affinity tag (termed Hupf1-2tag). Hupf1-2tag is localized in the cytoplasm similar to the endogenous Hupf1 protein, and the Hupf1-2tag cell line is fully NMD-competent. Using affinity chromatography, Hupf1-2tag-associated proteins were isolated. MS and immunoblotting identified the NMD factors Hupf2 and Hupf3a/b as interaction partners of Hupf1. Size-exclusion chromatography indicates that the NMD factors Hupf1, Hupf2 and the large isoform of Hupf3a might exist in a stable, high-molecular-mass complex of approx. 1.3 MDa. Interestingly, the poly(A)-binding protein was also identified by MS to be associated specifically with Hupf1-2tag. In contrast with the interaction with Hupf2 and Hupf3a/b, the association of poly(A)-binding protein with Hupf1 is highly sensitive to treatment of the isolated complexes with RNase. Components of the exon-exon junction complex or the translational eukaryotic release factor (eRF) 3 were not identified in complexes associated with Hupf1-2tag. We discuss these findings in the context of current models of NMD.

Base Sequence↗
PubMed2001

Sézary syndrome with a complex, frameshift p53 gene mutation in a Chernobyl survivor.

We report a case of Sézary syndrome in a patient who was in the immediate vicinity of the Chernobyl nuclear reactor accident 18 months prior to presentation. A complex, frameshift p53 gene mutation was subsequently identified in tumour tissue, consisting of an 8-base pair deletion and a T-->G point mutation in exon 7. This is characteristic of damage caused by ionizing radiation, which suggests a causal link between exposure to ionizing radiation and the subsequent development of Sézary syndrome, a rare form of T-cell leukaemia/lymphoma.

Gene Deletion↗
PubMed1970

Mechanics of frameshift mutagenesis in bacteriophage T4: role of chromosome tips.

In contrast to observations in bacteria and fungi, frameshift mutations in bacteriophage T4 do not arise during genetic recombination. Nascent mutants, captured in the heterozygous condition, exhibit properties which indicate that the new lesions are located at the extreme tips of the chromosomes, and are segregated by a combination of recombination and replication.

Acridines↗
PubMed1985

A frameshift mutation in the pre-S region of the human hepatitis B virus genome allows production of surface antigen particles but eliminates binding to polymerized albumin.

The coding region for the major polypeptide (p24S) of hepatitis B surface antigen (HBsAg) is preceded by an in-phase open reading frame termed pre-S. The coding potential of the pre-S region was examined in mouse L cells transformed with cloned hepatitis B virus DNA. Such cells produce three HBsAg-related polypeptides of Mr 24,000, 27,000, and 35,000 organized into complex particles of 22 nm diameter. These HBsAg particles bind to polymerized human albumin, but not to polyalbumins of several other species. In contrast, cells transformed with hepatitis B virus DNA bearing a frameshift mutation near the 3' end of the pre-S region secrete immunoreactive HBsAg particles containing only the 24,000 and 27,000 Mr species. These mutant particles, which lack the 35,000 Mr species, are unable to bind polymerized human albumin. These studies indicate that the pre-S region encodes the 35,000 Mr species, that this product accounts for the known polyalbumin-binding activity of HBsAg but is not required for assembly and secretion of HBsAg 22-nm particles, and that the major polypeptide of HBsAg is not derived primarily by cleavage of larger precursors encoded by the pre-S region.

DNA, Viral↗
PubMed1985

Bacterial peptide chain release factors: conserved primary structure and possible frameshift regulation of release factor 2.

Escherichia coli peptide chain release factors are proteins that direct the termination of translation in response to specific peptide chain termination codons. The mechanisms of codon recognition and peptidyl-tRNA hydrolysis are unknown. We have characterized the genes encoding release factor 1 (RF-1) and release factor 2 (RF-2) to study the structure-function relationships of the proteins and their regulation in the bacterium. In this report, we present the gene structure of RF-1 and RF-2, and a partial peptide sequence of RF-2. RF-1 and RF-2 are highly homologous in their primary structure. In addition, an in-frame premature opal (UGA) termination codon is located within the RF-2 coding region at amino acid position 26. This region of the protein was sequenced by automated Edman degradation to confirm the predicted reading frame, and a second independent isolate of the RF-2 gene was identified and sequenced to confirm the DNA sequence. These results imply that a frameshift occurs prior to the premature termination codon, thus allowing for translation of RF-2 to be completed. This may represent a mechanism of translational control of RF-2 expression. An alternative possible means of translational regulation is discussed.

Amino Acid Sequence↗
PubMed1989

Internal frameshifts within the mitochondrial genes for cytochrome oxidase subunit II and maxicircle unidentified reading frame 3 of Leishmania tarentolae are corrected by RNA editing: evidence for translation of the edited cytochrome oxidase subunit II mRNA.

The Leishmania tarentolae cytochrome oxidase (EC 1.9.3.1) subunit II (COII) and maxicircle unidentified reading frame 3 (MURF3) mRNAs are edited internally by the addition of four and five uridine residues, respectively, which eliminate -1 and +1 reading frameshifts in the gene sequences. The editing events in COII are conserved in three kinetoplastid species, and those in MURF3 are conserved in two species. A primer extension assay showed that the ratio of edited to unedited RNA differed for each gene: 89% of the COII and 36% of the MURF3 transcripts are edited. Preliminary evidence was obtained for translation of the edited COII transcript into protein: antibodies generated against a synthetic peptide with the predicted carboxyl-terminal amino acid sequence reacted with a polypeptide of the correct molecular weight in immunoblots of a mitochondrial lysate.

Amino Acid Sequence↗
PubMed1990

Broad spectrum of in vivo forward mutations, hypermutations, and mutational hotspots in a retroviral shuttle vector after a single replication cycle: substitutions, frameshifts, and hypermutations.

We determined the in vivo forward mutation rate in a single replication cycle for spleen necrosis virus (SNV). A method was developed to clone integrated proviruses of retroviral shuttle vectors by exploiting the tight binding of the lac operator to the lac repressor protein. The vectors contained the lacZ alpha gene as a reporter of mutations. Thirty-seven of the 16,867 proviruses recovered contained five classes of mutations, including substitutions and frameshifts. Runs of 9 and 10 identical base pairs and a direct repeat of 110 base pairs were mutational hotspots. In addition, two copies of a provirus contained 15 G-to-A substitutions. Such proviruses, which we name hypermutants, may arise through the action of an error-prone polymerase and could significantly contribute to the genetic variation in retroviral populations.

Animals↗
PubMed2000

Nonlinearity in genetic decoding: homologous DNA replicase genes use alternatives of transcriptional slippage or translational frameshifting.

The tau and gamma subunits of DNA polymerase III are both encoded by a single gene in Escherichia coli and Thermus thermophilus. gamma is two-thirds the size of tau and shares virtually all its amino acid sequence with tau. E. coli and T. thermophilus have evolved very different mechanisms for setting the approximate 1:1 ratio between tau and gamma. Both mechanisms put ribosomes into alternate reading frames so that stop codons in the new frame serve to make the smaller gamma protein. In E. coli, approximately 50% of initiating ribosomes translate the dnaX mRNA conventionally to give tau, but the other 50% shift into the -1 reading frame at a specific site (A AAA AAG) in the mRNA to produce gamma. In T. thermophilus ribosomal frameshifting is not required: the dnaX mRNA is a heterogeneous population of molecules with different numbers of A residues arising from transcriptional slippage on a run of nine T residues in the DNA template. Translation of the subpopulation containing nine As (or +/- multiples of three As) yields tau. The rest of the population of mRNAs (containing nine +/- nonmultiples of three As) puts ribosomes into the alternate reading frames to produce the gamma protein(s). It is surprising that two rather similar dnaX sequences in E. coli and T. thermophilus lead to very different mechanisms of expression.

Bacterial Proteins↗
PubMed2002

Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene.

Diesters of phthiocerol and phenolphthiocerol are important virulence factors of Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans. They are both long-chain beta-diols, and their biosynthetic pathway is beginning to be elucidated. Although the two classes of molecules share a common lipid core, phthiocerol diesters have been found in all the strains of the M. tuberculosis complex examined although phenolphthiocerol diesters are produced by only a few groups of strains. To address the question of the origin of this diversity 8 reference strains and 10 clinical isolates of M. tuberculosis were analyzed. We report the presence of glycosylated p-hydroxybenzoic acid methyl esters, structurally related to the type-specific phenolphthiocerol glycolipids, in the culture media of all reference strains of M. tuberculosis, suggesting that the strains devoid of phenolphthiocerol derivatives are unable to elongate the putative p-hydroxybenzoic acid precursor. We also show that all the strains of M. tuberculosis examined and deficient in the production of phenolphthiocerol derivatives are natural mutants with a frameshift mutation in pks15/1 whereas a single open reading frame for pks15/1 is found in Mycobacterium bovis BCG, M. leprae, and strains of M. tuberculosis that produce phenolphthiocerol derivatives. Complementation of the H37Rv strain of M. tuberculosis, which is devoid of phenolphthiocerol derivatives, with the fused pks15/1 gene from M. bovis BCG restored phenolphthiocerol glycolipids production. Conversely, disruption of the pks15/1 gene in M. bovis BCG led to the abolition of the synthesis of type-specific phenolphthiocerol glycolipid. These data indicate that Pks15/1 is involved in the elongation of p-hydroxybenzoic acid to give p-hydroxyphenylalkanoates, which in turn are converted, presumably by the PpsA-E synthase, to phenolphthiocerol derivatives.

Animals↗