Figure - uploaded by Thomas Liehr
Content may be subject to copyright.
Karyotype of patients showing in (A), FISH with whole chromosome paint 1 exclude the posibility of the missing material elsewhere in the genome (B) and subtelomeric FISH presenting in (C). Multicolor chromosome banding for Patient 1 clearly shows an extremely altered pattern on the derivative chromosome 1 (D). Using additional microdissection derived probes (MD45: stains 1pter-1p36.2, 1p35-1p33 and 1p22, MD50: stains 1q42-qter) in combination with a subtelomeric probe for chromosome 1qter (ST1q) or a partial chromosome paint for the long arm of chromosome 1 (pcp 1q) are shown in figure parts E and F, respectively (E-F). To control the results of array-CGH BAC RP11-960C20 in 1p34.2 was applied and confirmed deletion of the corresponding region on the derivatve chromosome 1. Thus, the derivative chromosome 1 could be described as der(1)(pter->p34.2::q43~44->p34.2:) (G).
Source publication
Genomic imbalances constitute a major cause of congenital and developmental abnormalities. GLUT1 deficiency syndrome is caused by various de novo mutations in the facilitated human glucose transporter 1 gene (1p34.2) and patients with this syndrome have been diagnosed with hypoglycorrhachia, mental and developmental delay, microcephaly and seizures...
Contexts in source publication
Context 1
... 46,XX, der(1)(pter->p34.2::q43~44- >p34.2:) ( Figure 3). FISH analysis using WCP probe excluded the possibility of a translocated material else- where in the genome. ...Similar publications
Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin prese...
Citations
... 5,17 En mucha menor medida se han reportado casos con grandes deleciones o duplicaciones, que incluso pueden involucrar el gen completo. 5,17,65,66 Se ha descrito cierto grado de asociación entre el tipo de variante patogénica y la gravedad del cuadro clínico, mientras que no se encontró relación entre el genotipo y el grado de respuesta a la DC. 4,5,23,38 De todas formas, cabe aclarar que el DFGLUT1 posee una gran heterogeneidad fenotípica e incluso pacientes con un mismo genotipo pueden presentar características clínicas muy diferentes. 5 48,49 b) Mecanismo de transporte simplificado. ...
... 5,17 More rarely, cases with large deletions or duplications, which may even involve the whole gene, have been reported. 5,17,65,66 An association has been described between the pathogenic variant and the severity of the clinical condition, while no correlation has been found between the genotype and the response to the KD. 4,5,23,38 Nevertheless, it is important to mention that GLUT1DS has a great phenotypic heterogeneity and even patients with the same genotype may have very different clinical features. ...
Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid,and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.
... Macf1 is not the only gene contained in the region of chromosome 1. Notable other genes found within the interstitial microdeletion reported by Dagklis et al. (Dagklis et al. 2016), for example, include GLUT1, which has been linked to hyperactivity and developmental delay (Vermeer et al. 2007;Aktas et al. 2010), the autism candidate gene RIMS3 ((Kumar et al. 2010), GRIK3, which is associated with developmental delay (Takenouchi et al. 2014), and AGO1/AGO3, which are linked with neurocognitive deficits (Tokita et al. 2015). Nearby microdeletions, such as a 1p34.3p34.2 ...
1p34.2p34.3 deletion syndrome is characterized by an increased risk for autism. Microtubule Actin Crosslinking Factor 1 (MACF1) is one candidate gene for this syndrome. It is unclear, however, how MACF1 deletion is linked to brain development and neurodevelopmental deficits. Here we report on Macf1 deletion in the developing mouse cerebral cortex, focusing on radial glia polarity and morphological integrity, as these are critical factors in brain formation. We found that deleting Macf1 during cortical development resulted in double cortex/subcortical band heterotopia as well as disrupted cortical lamination. Macf1-deleted radial progenitors showed increased proliferation rates compared to control cells but failed to remain confined within their defined proliferation zone in the developing brain. The overproliferation of Macf1-deleted radial progenitors was associated with elevated cell cycle speed and re-entry. Microtubule stability and actin polymerization along the apical ventricular area were decreased in the Macf1 mutant cortex. Correspondingly, there was a disconnection between radial glial fibers and the apical and pial surfaces. Finally, we observed that Macf1-mutant mice exhibited social deficits and aberrant emotional behaviors. Together, these results suggest that MACF1 plays a critical role in cortical progenitor proliferation and localization by promoting glial fiber stabilization and polarization. Our findings may provide insights into the pathogenic mechanism underlying the 1p34.2p34.3 deletion syndrome.
... Moreover, hypoglycorrhachia is observed in meningitis, meningeal carcinomatosis, subarachnoid hemorrhage, prolonged seizures or status epilepticus, and mitochondrial diseases (17,18). In suspected cases, the CSF/serum ratio of 0.33 to 0.37 is considered diagnostic for Glut1-DS (19). CSF lactate level of less than 1.4 mmol/l is another marker of Glut1-DS (20,21), and the results of a study in this regard showed that CSF lactate never elevates in Glut1-DS (22). ...
... GLUT1 deficiency has been described in detail in the previous sections of the article (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). ...
Epilepsy is a common neurological disorder in childhood with prominent neurological
manifestations, signs, and symptoms in inherited neurometabolic disorders.
Accurate diagnosis of neurometabolic disorders in epileptic patients increases the
possibility of a specific treatment to improve epilepsy. Therefore, early diagnosis is
essential in potentially treatable epileptic disorders. Various seizure types occur in
neurometabolic disorders, which are often refractory to antiepileptic drugs (without
the treatment of the underlying neurometabolic disorders). Patients with underlying
disorders have severe clinical presentations, such as refractory seizures. In addition,
they do not respond to antiepileptic drugs in many cases. In the epileptic patients
with developmental delay and/or regression, neurometabolic disorders should be
considered in the presence of abnormal neurological examination and brain imaging
with specific patterns. Some of these disorders are potentially treatable. Therefore,
neurologists should determine the etiology of epilepsy, especially in pediatric
patients, and the treatment should not be restricted to symptomatic therapy. The
present study aimed to introduce some of the treatable causes of epilepsy in pediatric
patients
... Furthermore, specific genes of this chromosomal region have been associated with distinct phenotypic malformations. More precisely, GLUT1 deficiency may cause a specific syndrome which correlates with hyperactivity and developmental delay [3,4], RIMS3 is considered to be a novel candidate for autism [5], GRIK3 has also been associated with developmental delay [6], and AGO1/AGO3 may be responsible for neurocognitive deficits [7]. Furthermore, the chromosomal region 1p34 has been characterized as a tumor suppressor gene locus suggesting a role in cancer development [8]. ...
BACKGROUND:
Interstitial microdeletions in 1p are extremely rare, as very few cases have been reported postnatally and only one prenatally, yet. There is a variability of phenotypic findings such as hypotonia, facial dysmorphisms, mild microcephaly, with being most common developmental delay.
CASE PRESENTATION:
The present case involved a female fetus with an interstitial deletion on 1p, presenting with micrognathia in the 2nd trimester routine ultrasound examination. Array-based comparative genomic hybridization (a-CGH) revealed a 2,7 Mb deletion located on 1p34.3 which could not be detected by standard karyotyping.
CONCLUSIONS:
This is the first prenatal case of an interstitial deletion in 1p34.3 with facial dysmorphism detected by a-CGH. Due to the use of a-CGH techniques submicroscopic imbalances could be detected, and a refined genotype-phenotype correlation could be achieved.
... 17 GLUT1 deficiency syndrome may also occur as a part of broader genetic syndromes, as seen in microdeletion syndromes involving the SLC2A1 gene. 18 ...
... Initially, a CSF-to-blood glucose ratio of 0.33-0.37 (CSF concentration 40 mg/dl) 18 was set as the cut-off value for a diagnosis of GLUT1DS in suspected cases. However, with the increasing recognition of milder allelic variants, higher values are now being applied (see Table 1). ...
Glucose transporter type 1 deficiency syndrome (GLUT1DS) is the result of impaired glucose transport into the brain. The "classic" GLUT1DS patient presents with infantile seizures (resistant to traditional seizure medications), developmental delay, acquired microcephaly, hypotonia, spasticity, and a complex movement disorder consisting of ataxia and dystonia. However, over the years, other clinical manifestations have been described, such as paroxysmal exertion-induced dystonia with or without seizures, choreoathetosis, alternating hemiplegia, and other paroxysmal events, such as intermittent ataxia, dystonia, and migraine. At the current state of the art in understanding of GLUT1DS, classifying the disease phenotype as "classical" or "non-classical" seems to be of limited clinical utility. It seems more appropriate to think in terms of a broad clinical spectrum in which we can observe intellectual impairment, acquired microcephaly, epilepsy, and movement disorders characterized by different clinical manifestations and degrees of severity. Lumbar puncture, a simple investigation, should be considered the first diagnostic step that, moreover, is feasible worldwide. Thereafter, mutational analysis of the solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) gene should be performed in patients with highly suggestive clinical findings and low cerebrospinal fluid glucose (<50mg/dl or ratio <0.60). Early diagnosis is critical because it allows prompt initiation of treatment with a ketogenic diet (KD). Childhood is the critical period for treatment of GLUT1DS: early diagnosis is crucial for an effective etiological therapy. KD treatment can be useful in adulthood too. Compliance has been found to be much better in GLUT1DS than in the other conditions for which KD treatment is indicated.
... Even though the primary goal of this mcb study was to delineate the karyotype, mcb results could be used to depict chromosomal gains and losses in NIH 3T3 (Fig. 3), as in comparative genomic hybridization (CGH) (Kallioniemi et al. 1992). This has not been done before for cell lines, but it is conceivable because imbalances detected by MCB in human patients have been confirmed by array-CGH, demonstrating the transferability of data from both approaches (Liehr et al. 2006; Aktas et al. 2010). Thus, 28% of the NIH 3T3 genome had loss and 12% gain of copy numbers. ...
Since being established in 1963, the murine fibroblast cell line NIH 3T3 has been used in thousands of studies. NIH 3T3 immortalized spontaneously and became tetraploid shortly after its establishment. Here we report the first molecular cytogenetic characterization of NIH 3T3 using fluorescence in situ hybridization based multicolor banding (mcb). Overall, a complex rearranged karyotype presenting 16 breakpoints was characterized. Also it was possible to deduce the resulting gains and losses of copy numbers in NIH 3T3. Overall, only 1.8% of the NIH 3T3 genome is disome, 26.2% tri-, 60% tetra-, 10.8% quinta-, and 1.2% hexasome. Strikingly, the cell line gained only 4 derivative chromosomes since its first cytogenetic description in 1989. An attempt to align the observed imbalances of the studied cell line with their homologous regions in humans gave the following surprising result: NIH 3T3 shows imbalances as typically seen in human solid cancers of ectodermal origin.
... Most tumors represent a mixture of different cell types, due to the normal complexity of the tissue, which includes aneuploidy and somatic genomic variation [3,4], as well as the complexity of tumors as they evolve from benign lesions to the more malignant, metastatic neoplasms [3,[5][6][7][8][9][10][11]. If researchers collect microarray data without confronting the problem of tumor or tissue heterogeneity, important correlations (e.g., between the spatial or temporal expression of several genes and the tumor or disease stage) might be missed [2,5,12]. ...
Many human tumors show significant changes in their signal transduction pathways and, thus, the way the cells interact with their environment. Often caused by chromosomal rearrangements, including gene amplifications, translocations or deletions, the altered levels of gene expression may provide a tumor-specific signature that can be exploited for diagnostic or therapeutic purposes. We investigated the utility of multiplexed fluorescence in situ hybridization (FISH) using non-isotopically labeled cDNA probes detected by Spectral Imaging as a sensitive and rapid procedure to measure tumor-specific gene expression signatures. We used a commercially available system to acquire and analyze multicolor FISH images. Initial investigations used panels of fluorescent calibration standards to evaluate the system. These experiments were followed by hybridization of five-to-six differently labeled cDNA probes, which target the transcripts of tyrosine kinase genes known to be differently expressed in normal cells and tumors of the breast or thyroid gland. The relatively simple, yet efficient, molecular cytogenetic method presented here may find many applications in characterization of solid tumors or disseminated tumor cells. Addressing tumor heterogeneity by means of multi-parameter single cell analyses is expected to enable a wide range of investigations in the areas of tumor stem cells, tumor clonality and disease progression.
... Genomic imbalances cause a clinical phenotype in a patient depending on the size and content of genes in the aberration . There is controversy about the genes in 1q44 responsible for agenesis of the corpus callosum891011121314. We present a case report of a female child with 54 Mb of 11qter duplication and 0.9 Mb of 1q44 deletion. ...
... Poot et al, 2008 [25] also rejected the AKT3 and ZNF238, as both the genes were not deleted in their study of a 4.8 deletion in 1q44 and the phenotypeincluded agenesis of corpus callosum. Aktas et al (2010) [13] detected a 2.7 Mb deletion in 1q44 starting from 244444664 bp to 247110269 bp, the distal breakpoint was located in ZNF672 and the proximal breakpoint was located in SMYD3. They concluded that Corpus callosum development is dependent on the critical genes lying in the short segment of 300 kb between the C1orf100 and C1orf121 in 1q44. ...
... They concluded that Corpus callosum development is dependent on the critical genes lying in the short segment of 300 kb between the C1orf100 and C1orf121 in 1q44. The present study reports a 1q44 deletion overlapping with the deletion reported by Aktas et al, 2010 . The proband had a smaller deletion of 0.9 Mb in 1q44 starting from 246,352,064 bp to247, 185,943 bp, the distal breakpoint was located in ZNF695 and the proximal breakpoint was located in SMYD3 gene as viewed in the UCSC genome browser http://genome.ucsc.edu ...
ABSTRACT:
Partial Trisomy 11q syndrome (or Duplication 11q) has defined clinical features and is documented as a rare syndrome by National Organization of Rare Disorders (NORD). Deletion 1q44 (or Monosomy 1q44) is a well-defined syndrome, but there is controversy about the genes lying in 1q44 region, responsible for agenesis of the corpus callosum. We report a female child with the rare Partial Trisomy 11q syndrome and Deletion 1q44 syndrome. The genomic imbalance in the proband was used for molecular characterization of the critical genes in 1q44 region for agenesis of corpus callosum. Some genes in 11q14q25 may be responsible for laryngomalacia.
We report a female child with dysmorphic features, microcephaly, growth retardation, seizures, acyanotic heart disease, and hand and foot deformities. She had agenesis of corpus callosum, laryngomalacia, anterior ectopic anus, esophageal reflux and respiratory distress. Chromosome analysis revealed a derivative chromosome 1. Her karyotype was 46,XX,der(1)t(1;11)(q44;q14)pat. The mother had a normal karyotype and the karyotype of the father was 46,XY,t(1;11)(q44;q14). SNP array analysis showed that the proband had a 54 Mb duplication of 11q14q25 and a 0.9 Mb deletion of the submicroscopic subtelomeric 1q44 region. Fluorescence Insitu Hybridisation confirmed the duplication of 11qter and deletion of 1qter.
Laryngomalacia or obstruction of the upper airway is the outcome of increased dosage of some genes due to Partial Trisomy 11q Syndrome. In association with other phenotypic features, agenesis of corpus callosum appears to be a landmark phenotype for Deletion 1q44 syndrome, the critical genes lying proximal to SMYD3 in 1q44 region.
... Some chromosomal deletions mapped to this region were recently identified in patients with inherited disorders (e.g. Dandy-Walker complex) (Poot et al., 2007;van Bon et al., 2008;Aktas et al., 2010). The clinical phenomena as a consequence of KLP6 deficiency are intriguing. ...
Mitochondria utilize diverse cytoskeleton-based mechanisms to control their functions and morphology. Here, we report a role for kinesin-like protein KLP6, a newly identified member of the kinesin family, in mitochondrial morphology and dynamics. An RNA interference screen using Caenorhabditis elegans led us to identify a C. elegans KLP-6 involved in maintaining mitochondrial morphology. We cloned a cDNA coding for a rat homolog of C. elegans KLP-6, which is an uncharacterized kinesin in vertebrates. A rat KLP6 mutant protein lacking the motor domain induced changes in mitochondrial morphology and significantly decreased mitochondrial motility in HeLa cells, but did not affect the morphology of other organelles. In addition, the KLP6 mutant inhibited transport of mitochondria during anterograde movement in differentiated neuro 2a cells. To date, two kinesins, KIF1Bα and kinesin heavy chain (KHC; also known as KIF5) have been shown to be involved in the distribution of mitochondria in neurons. Expression of the kinesin heavy chain/KIF5 mutant prevented mitochondria from entering into neurites, whereas both the KLP6 and KIF1Bα mutants decreased mitochondrial transport in axonal neurites. Furthermore, both KLP6 and KIF1Bα bind to KBP, a KIF1-binding protein required for axonal outgrowth and mitochondrial distribution. Thus, KLP6 is a newly identified kinesin family member that regulates mitochondrial morphology and transport.
