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PubMed2026

Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder.

Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous EIF1AX variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of EIF1AX variants was evaluated using a molecular dynamic simulation and transgenic Drosophila models. We identified four de novo hemizygous EIF1AX variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic Drosophila harboring wild-type (WT) EIF1AX or the three other EIF1AX missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the Drosophila optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.

Humans↗

PubMed1991

Functional connections in the human temporal lobe. II. Evidence for a loss of functional linkage between contralateral limbic structures.

In a previous investigation of functional limbic pathways in the human mesial temporal lobe, we found evidence for strong connections between ipsilateral mesial temporal structures, but none for contralateral functional connections (Wilson et al. 1990). In the present study, we focused specifically upon the question of functional commissural linkages between these structures by systematic stimulation of a total of 390 electrode placements in 74 epileptic patients with temporal lobe depth electrodes implanted for surgical diagnosis. Eight standard electrode placement regions were targeted: amygdala, entorhinal cortex, anterior, middle and posterior hippocampus, subicular cortex, middle parahippocampal gyrus, and posterior parahippocampal gyrus. Three to six electrodes were implanted bilaterally in each patient, and each electrode was individually stimulated while recording from all the other sites. Out of the 390 electrodes stimulated, 78% were effective in evoking clear responses in adjacent ipsilateral structures, and 75% of 581 ipsilateral recording sites were responsive to stimulation. Only one of the stimulated electrode sites was effective in evoking responses in contralateral recording sites, and only two of 511 contralateral recording sites were responsive to that stimulation. The effective stimulation site was in presubicular cortex, and the responsive contralateral recording sites were in entorhinal and presubicular cortices. Response to this stimulation site was intermittent and variable in latency. The relative ease of obtaining functional verification of significant ipsilateral anatomical pathways in the human limbic system, and the sharply contrasting difficulty of functionally activating commissural pathways to contralateral limbic sites are discussed in the context of decreases in hippocampal contribution to commissural pathways in the primate brain compared to sub-primate mammals, and the significance of this change to normal limbic system function as well as to mechanisms of seizure spread in epilepsy.

Amygdala↗

PubMed2001

Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1.

The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.

Alleles↗

PubMed1992

Molecular basis of loss-of-function mutations in the glp-1 gene of Caenorhabditis elegans.

The glp-1 gene encodes a membrane protein required for inductive cell interactions during development of the nematode Caenorhabditis elegans. Here we report the molecular characterization of 15 loss-of-function (lf) mutations of glp-1. Two nonsense mutations appear to eliminate glp-1 activity; both truncate the glp-1 protein in its extracellular domain and have a strong loss-of-function phenotype. Twelve missense mutations and one in-frame deletion map to sites within the repeated motifs of the glp-1 protein (10 epidermal growth factor [EGF]-like and 3 LNG repeats extracellularly and 6 cdc10/SWI6, or ankyrin, repeats intracellularly). We find that all three types of repeated motifs are critical to glp-1 function, and two individual EGF-like repeats may have distinct functions. Intriguingly, all four missense mutations in one phenotypic class map to the N-terminal EGF-like repeats and all six missense mutations in a second phenotypic class reside in the intracellular cdc10/SWI6 repeats. These two clusters of mutations may identify functional domains within the glp-1 protein.

Amino Acid Sequence↗

PubMedDate not supplied

Loss of function of the tissue specific transcription factor HNF1 alpha in renal cell carcinoma and clinical prognosis.

BACKGROUND: Human renal cell carcinogenesis is associated with loss of expression of tissue-specific genes and loss of function of tissue-specific transcription factors such as HNF(hepatic nuclear factor)1 alpha. MATERIALS AND METHODS: In this study HNF1 alpha DNA-binding activities and protein amounts were determined by gel retardation assay and Western blot analysis, respectively, in 42 non-metastasized renal cell carcinomas and paired normal tissues. RESULTS: 36 tumors out of 42 (86%) showed diminished binding activity of HNF1 alpha. In most cases (26 out of 42) this appeared to be due to decreased amounts of HNF1 alpha protein, but 10 tumors contained equal or even higher amounts of HNF1 alpha, in spite of reduced binding to DNA. Only 6 tumors out of 42 had unaltered HNF1 alpha binding activity. A clinical follow-up was obtained for 40 patients. Over an average follow-up period of 39 months no significant differences in the survival rate were observed between patients having lost or retained HNF1 alpha function. However, since most of the patients with retained function are still alive, long-term follow-up might be warranted. CONCLUSIONS: The very high incidence of loss of HNF1 alpha function indicates the important biological role of this change in renal cell carcinoma.

Adult↗

PubMed2003

"Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis.

Several genetic factors have been well known to predispose one to chronic pancreatitis (CP). However, little is known about the genetic factors that may provide a protective effect against the disease. Having found a nonsense mutation (c.111C>A; Y37X) and a splicing mutation (IVS2+1G>A) in the cationic trypsinogen gene (protease, serine, 1; PRSS1) in alcoholics without the development of CP, but not in alcoholics with CP and patients with hereditary or idiopathic CP, we propose that while "gain of function" mutations in the PRSS1 gene predispose one to pancreatitis, "loss of function" mutations in the gene may protect one against the disease.

Adult↗

PubMed2000

Effects of loss-of-function and gain-of-function mutations of c-kit on the gastrointestinal tract.

Protooncogene c-kit encodes a receptor tyrosine kinase, KIT. Interstitial cells of Cajal (ICCs) that are important for the autonomous movement of the gastrointestinal tract essentially require the normal function of the KIT for their development. Therefore, germline loss-of-function mutations of the c-kit gene cause deficiency of ICCs that results in disturbed gastrointestinal movement. On the other hand, somatic gain-of-function mutations of the c-kit gene induce gastrointestinal stromal tumors (GIST) that are considered to originate from ICCs. Moreover, germline gain-of-function mutations of the c-kit gene are a cause of familial development of multiple GISTs.

Animals↗

PubMed1998

Suppression of an Hsp70 mutant phenotype in Saccharomyces cerevisiae through loss of function of the chromatin component Sin1p/Spt2p.

The Ssa subfamily of Hsp70 molecular chaperones in the budding yeast Saccharomyces cerevisiae has four members, encoded by SSA1, SSA2, SSA3, and SSA4. Deletion of the two constitutively expressed genes, SSA1 and SSA2, results in cells which are slow growing and temperature sensitive. In this study, we demonstrate that an extragenic suppressor of the temperature sensitivity of ssa1 ssa2 strains, EXA1-1, is a loss-of-function mutation in SIN1/SPT2, which encodes a nonhistone component of chromatin. Loss of function of Sin1p leads to overexpression of SSA3 in the ssa1 ssa2 mutant background, at a level which is sufficient to mediate suppression. In a strain which is wild type for SSA genes, we detected no effect of Sin1p on Ssa3p expression except under conditions of heat shock. Existing data indicate that expression of SSA3 in the ssa1 ssa2 mutant background as well as in heat-shocked wild-type strains is mediated by the heat shock transcription factor HSF. Our findings suggest that it is HSF-mediated induction of SSA3 which is modulated by Sin1p. The EXA1-1 suppressor mutation thus improves the growth of ssa1 ssa2 strains by selectively increasing HSF-mediated expression of SSA3.

Bacterial Proteins↗

PubMed2002

A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocytic leukaemia: a molecular study.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) has a familial incidence nearly three times higher than expected for the general population and one predisposing factor might be an inherited failure of mechanisms involved in apoptosis of lymphocytes. Our aim was to ascertain whether or not a defect in a proapoptotic pathway, caused by a single nucleotide polymorphism that results in loss-of-function of P2X7 in healthy individuals, was present in leukaemic B lymphocytes of patients with CLL. METHODS: We extracted genomic DNA from the peripheral blood leucocytes of 36 unrelated individuals with CLL, four individuals with familial CLL, and 46 age-matched controls. We sequenced a PCR product to detect mutations in exon 13 of P2X7. In most patients with CLL, we measured expression and function of the P2X7 receptor by flow cytometry in B lymphocytes and T lymphocytes. FINDINGS: The prevalence of the polymorphic mutation and the frequency of the mutant allele were three-fold greater in individuals with CLL than in white, elderly controls. Individuals homozygous for the polymorphic allele had no P2X7 receptor function and heterozygotes had half the mean function of that seen in individuals homozygous for the wildtype allele; amounts of ATP-induced apoptosis varied accordingly. In two families, in which we studied a father-son pair and a sister-sister pair with CLL, loss of P2X7 function arose because of inheritance of one or two 1513A-->C alleles for P2X7. INTERPRETATION: Activation of the P2X7 receptor leads to apoptosis of lymphocytes in individuals with CLL, and reduced function of this receptor has an anti-apoptotic effect, resulting in an increase in B-cell numbers. Thus, inheritance of a loss-of-function polymorphic mutation at position 1513 in the P2X7 gene could contribute to the pathogenesis of CLL.

Aged↗

PubMed2006

A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer.

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin--Vps17p--is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.

Carrier Proteins↗

PubMed2025

Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.

PURPOSE: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies. METHODS: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle computed tomography or magnetic resonance imaging, and muscle biopsy findings were collected and standardized. SPTAN1 protein, messenger RNA expression analysis and copy DNA sequencing was performed on muscle tissue from 2 participants. RESULTS: Five families showed autosomal dominant mode of inheritance, whereas in 9 patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In 2 families, further segregation analysis was not possible. All affected participants presented with early childhood-onset distal weakness and foot abnormalities. Muscle magnetic resonance imaging or computed tomography in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense-mediated decay in muscle tissue derived from 2 patients. CONCLUSION: We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.

Humans↗

PubMed2004

In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation.

Heterozygous loss-of-function mutations in ZIC2 result in the severe brain malformation known as holoprosencephaly (HPE), indicating that forebrain development is exquisitely sensitive to the activity of this poorly understood transcription factor. To identify the regions of ZIC2 that are essential for activity, we have assessed the ability of a variety of ZIC2 mutant proteins to function in in vitro assays. Two sources of information were used to design relevant mutations. First, phenotype producing mutations in human and in mouse ZIC2 were mimicked and secondly, a comparative sequence analysis of the C-terminal was carried out. Analysis of these mutations suggests that either a decrease or an increase in ZIC2 mediated transcriptional activity can produce a forebrain phenotype. In addition, the analysis reveals that the C-terminal of ZIC2 contains both activation and repression domains. This region of ZIC2 contains an alanine-tract, and expansion of this domain is associated with HPE. In vitro analysis of proteins with alterations in alanine-tract length illustrates that the C-terminal alanine-tract of ZIC2 influences the strength of DNA binding and alters transcriptional activity in a promoter-specific manner. This finding provides a possible mechanism by which alanine-tract expansion mutations could alter the function of other transcription factors.

Alanine↗

PubMed2005

Loss of function of OsDCL1 affects microRNA accumulation and causes developmental defects in rice.

MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) are two types of noncoding RNAs involved in developmental regulation, genome maintenance, and defense in eukaryotes. The activity of Dicer or Dicer-like (DCL) proteins is required for the maturation of miRNAs and siRNAs. In this study, we cloned and sequenced 66 candidate rice (Oryza sativa) miRNAs out of 1,650 small RNA sequences (19 to approximately 25 nt), and they could be further grouped into 21 families, 12 of which are newly identified and three of which, OsmiR528, OsmiR529, and OsmiR530, have been confirmed by northern blot. To study the function of rice DCL proteins (OsDCLs) in the biogenesis of miRNAs and siRNAs, we searched genome databases and identified four OsDCLs. An RNA interference approach was applied to knock down two OsDCLs, OsDCL1 and OsDCL4, respectively. Strong loss of function of OsDCL1IR transformants that expressed inverted repeats of OsDCL1 resulted in developmental arrest at the seedling stage, and weak loss of function of OsDCL1IR transformants caused pleiotropic developmental defects. Moreover, all miRNAs tested were greatly reduced in OsDCL1IR but not OsDCL4IR transformants, indicating that OsDCL1 plays a critical role in miRNA processing in rice. In contrast, the production of siRNA from transgenic inverted repeats and endogenous CentO regions were not affected in either OsDCL1IR or OsDCL4IR transformants, suggesting that the production of miRNAs and siRNAs is via distinct OsDCLs.

Arabidopsis Proteins↗

PubMed2006

Melanocortin-1 receptor: loss of function mutations and skin cancer.

We present a red-haired patient who came to our clinic seeking information regarding his predisposition to skin cancer. We discuss the receptor involved in hair color and the allelic variants that lead to red hair. These variants are often characterized by loss of function mutations, which lead to a predisposition to non-melanoma skin cancers, with relative risks reaching as high as a 6.7 in one study. Most concerning, however, is that some of these loss of function mutations may act synergistically with genetic mutations that cause familial melanomas. Thus, red haired patients with familial melanoma syndromes have a greater risk of melanoma than those patients with familial melanoma syndromes alone.

Adult↗

PubMed2002

The role of myocardial KATP-channel blockade in the protective effects of glibenclamide against ischaemia in the rat heart.

Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of KATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of KATP channels, opening of these KATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 micromol x l(-1); n = 5), the KATP channel openers pinacidil (1 micromol x (l-1); n = 5) and diazoxide (30 micromol x l(-1); n = 5), the combination of glibenclamide with pinacidil (n = 5) and glibenclamide with diazoxide (n = 5), and vehicle (n = 8). Both pinacidil and diazoxide significantly increased coronary blood flow 2-3 times, which was abolished by glibenclamide pre- and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks KATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2 +/- 2.9% during vehicle. Glibenclamide reduced the cardiac functional loss to 4.3 +/- 1.2% (P < 0.01). Interestingly, both pinacidil and diazoxide reduced the cardiac functional loss to 4.0 +/- 1.5% (P < 0.01) and 2.9 +/- 1.4% (P < 0.001), respectively. The combination pinacidil+glibenclamide resulted in additional protection compared with the individual components (0.6 +/- 0.1 versus 4.0 +/- 1.5%, P < 0.05). Thus, in contrast to its effect on coronary vascular tone, the glibenclamide-induced improvement of postischaemic cardiac function may not be mediated through blockade of the KATP channel. Alternative mechanisms may be operative, such as uncoupling of the mitochondrial respiratory chain, thereby preconditioning the hearts against stunning.

Animals↗

PubMed1975

[Function of external respiration and hemodynamics of the lesser blood circulation circuit in lung cancer patients].

Bronchospirometric studies of the ventilatory function in 200 patients with pulmonary cancer inducated a dependence between functional losses in the involved lung and tumor localization, and the functional importance of the bronchus involved. A central localization of the tumor results in more pronounced functional losses in gas metabolism, in particular, that, as evidenced by rheographic findings, is conditioned by both the reduced ventilation and blood flow in the affected lung. The results of investigations have indicated that in 80% of patients the rate of functional losses and their distribution between the involved and intact lung allowed an accomplishment of an operative intervention such as pneumonectomy.

Adult↗

PubMed2024

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.

PURPOSE: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings. METHODS: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort. RESULTS: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. CONCLUSION: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.

Humans↗

PubMed2025

Biallelic loss-of-function variants in C19orf44 lead to retinal degeneration.

BACKGROUND: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs. METHODS: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants. RESULTS: Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in C19orf44 (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs*2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390*/c.976_977del;p.Leu326Lysfs*15). CONCLUSIONS: Our findings establish C19orf44 as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.

Humans↗