scholarly journals Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis.

10.1242/jcs.250902 â—½  
2021 â—½  
Author(s):  
Gianmarco Pallavicini â—½  
Marta Gai â—½  
Giorgia Iegiani â—½  
Gaia Elena Berto â—½  
Annie Adrait â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
Hirschsprung Disease â—½  
Facial Features â—½  
Gene Encoding â—½  
Physiological Conditions â—½  
Recessive Mutations â—½  
Microtubule Stability â—½  
Chromosome Passenger Complex â—½  
Syndrome Protein â—½  
Kinesin Family

Goldberg-Shprintzen disease (GOSHS) is a rare microcephaly syndrome accompanied by intellectual disability, dysmorphic facial features, peripheral neuropathy and Hirschsprung disease. It is associated with recessive mutations in the gene encoding kinesin family member 1-binding protein (KIF1BP). The encoded protein regulates axon microtubules dynamics, kinesin attachment and mitochondrial biogenesis, but it is not clear how its loss could lead to microcephaly. We identified KIF1BP in the interactome of Citron Kinase (CITK), a protein produced by primary hereditary microcephaly 17 (MCPH17) gene. KIF1BP and CITK interact under physiological conditions in mitotic cells. Similar to CITK, KIF1BP is enriched at the midbody ring and is required for cytokinesis. The association between KIF1BP and CITK can be influenced by CITK activity and the two proteins may antagonize each other for their midbody localization. KIF1BP knockdown decreases microtubule stability, increases KIF23 midbody levels and impairs midbody localization of KIF14, as well as of Chromosome Passenger Complex. These data indicate that KIF1BP is a CITK interactor involved in midbody maturation and abscission and suggest that cytokinesis failure may contribute to the microcephaly phenotype observed in GOSHS.

scholarly journals Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome

2021 â—½  
Author(s):  
Aleksandra Jakubiak â—½  
Krzysztof Szczałuba â—½  
Magdalena Badura-Stronka â—½  
Anna Kutkowska-Kaźmierczak â—½  
Anna Jakubiuk-Tomaszuk â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
Congenital Anomalies â—½  
Chromosomal Region â—½  
Neurodevelopmental Disorder â—½  
Hirschsprung Disease â—½  
Psychomotor Retardation â—½  
Facial Features â—½  
Dysmorphic Features â—½  
Pathogenic Variants â—½  
Intragenic Deletions

AbstractMowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.

Overproduction of yeast viruslike particles by strains deficient in a mitochondrial nuclease

1989 â—½  
Vol 9 (8) â—½  
pp. 3323-3331
Author(s):  
Y X Liu â—½  
C L Dieckmann
Keyword(s):  
Coat Protein â—½  
Killer Toxin â—½  
Nuclear Gene â—½  
Fold Increase â—½  
Mitochondrial Outer Membrane â—½  
Gene Encoding â—½  
Recessive Mutations â—½  
A Genome â—½  
Nonfermentable Carbon Source â—½  
Viruslike Particles

Saccharomyces cerevisiae strains are often host to several types of cytoplasmic double-stranded RNA (dsRNA) genomes, some of which are encapsidated by the L-A dsRNA product, an 86,000-dalton coat protein. Here we present the finding that nuclear recessive mutations in the NUC1 gene, which encodes the major nonspecific nuclease of yeast mitochondria, resulted in at least a 10-fold increase in amounts of the L-A dsRNA and its encoded coat protein. The effect of nuc1 mutations on L-A abundance was completely suppressed in strains that also hosted the killer-toxin-encoding M dsRNA. Both NUC1 and nuc1 strains containing the L-A genome exhibited an increase in coat protein abundance and a concomitant increase in L-A dsRNA when the cells were grown on a nonfermentable carbon source rather than on glucose, an effect independent of the increase in coat protein due to nuc1 mutations or to the absence of M. The increase in L-A expression in nuc1 strains was similar to that observed in strains with mutations in the nuclear gene encoding the most abundant outer mitochondrial membrane protein, porin. nuc1 mutations did not affect the level of porin in the mitochondrial outer membrane. Since the effect of mutations in nuc1 was to alter the copy number of the L-A coat protein genome rather than to change the level of the M toxin genome (as do mak and ski mutations), these mutations define a new class of nuclear genes affecting yeast dsRNA abundance.

WED 202 Lamb-shaffer syndrome: importance of snp array in diagnosing neurodevelopmental syndromes

2018 â—½  
Vol 89 (10) â—½  
pp. A29.4-A30 â—½  
Author(s):  
Ela M Akay â—½  
Ian S Schofield â—½  
Ming H Lai â—½  
Rhys H Thomas
Keyword(s):  
Intellectual Disability â—½  
Language Impairment â—½  
Cervical Vertebrae â—½  
Snp Array â—½  
Global Developmental Delay â—½  
Prior History â—½  
Loss Of Function â—½  
Mild Intellectual Disability â—½  
Gene Encoding â—½  
Original Cohort

We describe the seizure phenotype of a 26 year old lady who presented with a probable photic-induced convulsion on a background of mild intellectual disability, facial dysmorphia, fused cervical vertebrae and ventricular septal defect. There was no prior history of seizures.Routine EEG was polyrhythmic with a prominent photoparoxysmal response at 14 Hz and 40 Hz. CT head was normal. A SNP array demonstrated a rare 51 kb deletion at 12 p12.1 which disrupts the SOX5 gene.SOX5 is a developmentally important gene encoding a transcription factor that plays a role in multiple developmental pathways including of the nervous system. Loss of function of this gene is associated with Lamb-Shaffer syndrome, first characterised in 2012 with global developmental delay, intellectual disability, mild dysmorphic facies, language impairment and variable skeletal abnormalities.3 of the original cohort of 16 patients described experienced seizures and the nature of their epilepsy was not further defined. Only a further 7 cases have been reported to date, none of whom experienced seizures. Our case helps to broaden the phenotype of Lamb-Shaffer syndrome, highlights the importance of looking for copy number variation and poses questions regarding the neurobiology of photo-sensitivity.

scholarly journals Intronic Variant in CNTNAP2 Gene in a Boy With Remarkable Conduct Disorder, Minor Facial Features, Mild Intellectual Disability, and Seizures

2020 â—½  
Vol 8 â—½  
Author(s):  
Raffaele Falsaperla â—½  
Xena Giada Pappalardo â—½  
Catia Romano â—½  
Simona Domenica Marino â—½  
Giovanni Corsello â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
Conduct Disorder â—½  
Facial Features â—½  
Mild Intellectual Disability

scholarly journals A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2 , a Gene Encoding a Component of the TTT Complex

2016 â—½  
Vol 98 (5) â—½  
pp. 909-918 â—½  
Author(s):  
Jing You â—½  
Nara L. Sobreira â—½  
Dustin L. Gable â—½  
Julie Jurgens â—½  
Dorothy K. Grange â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
Gene Encoding

Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy—Expanding the differential diagnosis for pachyonychia congenita

2013 â—½  
Vol 70 (1) â—½  
pp. 58-60 â—½  
Author(s):  
Neil J. Wilson â—½  
C. David Hansen â—½  
Dilek Azkur â—½  
Can N. Kocabas â—½  
Ayse Metin â—½  
...  
Keyword(s):  
Differential Diagnosis â—½  
Nail Dystrophy â—½  
Gene Encoding â—½  
Recessive Mutations â—½  
Pachyonychia Congenita

scholarly journals WNK4 Kinase: from structure to physiology

2021 â—½  
Author(s):  
Adrian Rafael Murillo-de-Ozores â—½  
Alejandro Rodriguez-Gama â—½  
Hector Carbajal-Contreras â—½  
Gerardo Gamba â—½  
Maria Castaneda-Bueno
Keyword(s):  
Oxidative Stress â—½  
Mouse Models â—½  
Serine Threonine Kinase â—½  
Gene Encoding â—½  
Threonine Kinase â—½  
Physiological Conditions â—½  
Different Levels â—½  
Familial Hyperkalemic Hypertension

With No Lysine (K) kinase 4 (WNK4) belongs to a serine-threonine kinase family characterized by the atypical positioning of its catalytic lysine. Despite the fact that WNK4 has been found in many tissues, the majority of its study has revolved around its function in the kidney, specifically as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. This is explained by the description of gain-of-function mutations in the gene encoding WNK4 that cause Familial Hyperkalemic Hypertension (FHHt). This disease is mainly driven by increased downstream activation of the Ste20-related Proline Alanine Rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1)-NCC pathway, which increases salt reabsorption in the DCT and indirectly impairs renal K+ secretion. Here, we review the large volume of information that has accumulated about different aspects of WNK4 function. We first review the knowledge on WNK4 structure and enumerate the functional domains and motifs that have been characterized. Then, we discuss WNK4 physiological functions based on the information obtained from in vitro studies and from a diverse set of genetically modified mouse models with altered WNK4 function. We then review in vitro and in vivo evidence on the different levels of regulation of WNK4. Finally, we go through the evidence that has suggested how different physiological conditions act through WNK4 to modulate NCC activity.

scholarly journals Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

eLife â—½  
10.7554/elife.57190 â—½  
2020 â—½  
Vol 9 â—½  
Author(s):  
Evelien Van Hoeymissen â—½  
Katharina Held â—½  
Ana Cristina Nogueira Freitas â—½  
Annelies Janssens â—½  
Thomas Voets â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
De Novo â—½  
Epileptic Activity â—½  
Gene Encoding â—½  
Epileptic Encephalopathies â—½  
Channel Function â—½  
Functional Consequences â—½  
Altered Response â—½  
Voltage Sensor Domain â—½  
Higher Sensitivity

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulfate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.

scholarly journals MED13L-related intellectual disability due to paternal germinal mosaicism

10.1101/mcs.a006124 â—½  
2021 â—½  
pp. mcs.a006124
Author(s):  
Beata Bessenyei â—½  
Istvan Balogh â—½  
Attila Mokanszki â—½  
Aniko Ujfalusi â—½  
Rolph Pfundt â—½  
...  
Keyword(s):  
Intellectual Disability â—½  
De Novo â—½  
Mediator Complex â—½  
Facial Dysmorphism â—½  
Facial Features â—½  
Speech Delay â—½  
Motor Delay â—½  
First Case â—½  
Intragenic Deletion â—½  
Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

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