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Warburg micro syndrome

D Kabzińska, H Mierzewska, J Senderek, A Kochański
The Warburg micro syndrome (WARBM) is a genetically heterogeneous syndrome linked to at least 4 loci. At the clinical level, WARBM is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, severe mental retardation, and hypogonadism. In some families additional clinical features have been reported. The presence of uncommon clinical features (peripheral neuropathy, cardiomyopathy) may result in misdirected molecular diagnostics. Using the next generation sequencing approach (NGS), we were able to diagnose WARBM1 syndrome by detection of a new mutation within the RAB3GAP1 gene...
2016: Folia Neuropathologica
D J Sidjanin, Anna K Park, Adam Ronchetti, Jamaria Martins, William T Jackson
In humans, loss of TBC1D20 (TBC1 domain family, member 20) protein function causes Warburg Micro syndrome 4 (WARBM4), an autosomal recessive disorder characterized by congenital eye, brain, and genital abnormalities. TBC1D20-deficient mice exhibit ocular abnormalities and male infertility. TBC1D20 is a ubiquitously expressed member of the family of GTPase-activating proteins (GAPs) that increase the intrinsically slow GTP-hydrolysis rate of small RAB-GTPases when bound to GTP. Biochemical studies have established TBC1D20 as a GAP for RAB1B and RAB2A...
October 2, 2016: Autophagy
Marie Trkova, Martin Hynek, Lubica Dudakova, Vera Becvarova, Martin Hlozanek, Dagmar Raskova, Andrea L Vincent, Petra Liskova
We observed bilateral cataracts on second trimester ultrasound, in two consecutive pregnancies, with no other structural defects detected. The parents were unrelated and had no family history for the disease. The first pregnancy was terminated in week 22. Copy number variation analysis revealed, in both the aborted fetus and the mother, a 495 kb duplication at 22q11.23 encompassing CRYBB3 and CRYBB2, and not present in variation databases. In the second pregnancy, lens hyperechogenicity was detected by ultrasound at week 13 and 4 days...
July 2016: American Journal of Medical Genetics. Part A
Prabhjot Kaur Sekhon, R Premalatha, Sarala Sabapathy
Warburg syndrome is a rare disorder characterized by microcephaly, microcornea, congenital cataract, developmental delay, and hypogonadism. Here, we report two siblings from India who presented with developmental delay, microcornea, microphthalmia, and bilateral congenital cataracts, born to the third-degree consanguineously married couple. Both children had hypoplasia of corpus callosum. In this report, we aim to highlight and compare clinical features of these two cases with previously reported cases.
January 2016: Journal of Pediatric Neurosciences
Qinwei Wu, Xiaqin Sun, Weihua Yue, Tianlan Lu, Yanyan Ruan, Tianda Chen, Dai Zhang
BACKGROUND: Loss of function mutations in RAB18, has been identified in patients with the human neurological and developmental disorder Warburg Micro syndrome. However, the function of RAB18 in brain remains unknown. RESULTS: In this study, we report that RAB18 is a critical regulator of neuronal migration and morphogenesis. Using in utero electroporation suppression of RAB18 in the mouse brain impairs radial migration. Overexpression of dominant negative RAB18 or disruption of RAB3GAP (RAB18GEF) also results in delayed neuronal migration in the developing mouse cortex and inhibition of neurite growth in vitro...
2016: Molecular Brain
Tendai Mhlanga-Mutangadura, Gary S Johnson, Robert D Schnabel, Jeremy F Taylor, Gayle C Johnson, Martin L Katz, G Diane Shelton, Teresa E Lever, Elizabeth Giuliano, Nicolas Granger, Jeremy Shomper, Dennis P O'Brien
An autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells...
February 2016: Neurobiology of Disease
Michaela Wiedmer, Anna Oevermann, Stephanie E Borer-Germann, Daniela Gorgas, G Diane Shelton, Michaela Drögemüller, Vidhya Jagannathan, Diana Henke, Tosso Leeb
We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene...
November 23, 2015: G3: Genes—Genomes—Genetics
Priyanka Srivastava, Deepti Saxena, Stephen Joshi, Shubha R Phadke
History of consanguinity is important in monogenic disorders as it supports autosomal recessive mode of inheritance. This case report illustrates the use of homozygosity mapping using single nucleotide polymorphism (SNP) microarray data to identify the causative gene in a case with Warburg Micro syndrome (WARBM). This syndrome has non-specific features like microcephaly and cataract; etiological diagnosis based on clinical features is not possible. Four causative genes are known for WARBM syndrome. In such a situation of autosomal recessive disorders of heterogeneous etiologies, SNP microarray and homozygosity mapping is a useful and cost effective strategy...
March 2016: Indian Journal of Pediatrics
Mark T Handley, Sarah M Carpanini, Girish R Mali, Duska J Sidjanin, Irene A Aligianis, Ian J Jackson, David R FitzPatrick
RAB18, RAB3GAP1, RAB3GAP2 and TBC1D20 are each mutated in Warburg Micro syndrome, a rare autosomal recessive multisystem disorder. RAB3GAP1 and RAB3GAP2 form a binary 'RAB3GAP' complex that functions as a guanine-nucleotide exchange factor (GEF) for RAB18, whereas TBC1D20 shows modest RAB18 GTPase-activating (GAP) activity in vitro. Here, we show that in the absence of functional RAB3GAP or TBC1D20, the level, localization and dynamics of cellular RAB18 is altered. In cell lines where TBC1D20 is absent from the endoplasmic reticulum (ER), RAB18 becomes more stably ER-associated and less cytosolic than in control cells...
June 2015: Open Biology
Lina Basel-Vanagaite, Pola Smirin-Yosef, Jenna Lee Essakow, Shay Tzur, Irina Lagovsky, Idit Maya, Metsada Pasmanik-Chor, Adva Yeheskel, Osnat Konen, Naama Orenstein, Monika Weisz Hubshman, Valerie Drasinover, Nurit Magal, Gaby Peretz Amit, Yael Zalzstein, Avraham Zeharia, Mordechai Shohat, Rachel Straussberg, Didier Monté, Mali Salmon-Divon, Doron M Behar
Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village...
June 2015: Human Genetics
Chih-Ya Cheng, Jaw-Ching Wu, Jin-Wu Tsai, Fang-Shin Nian, Pei-Chun Wu, Lung-Sen Kao, Ming-Ji Fann, Shih-Jen Tsai, Ying-Jay Liou, Chin-Yin Tai, Chen-Jee Hong
Mutations in the gene of RAB18, a member of Ras superfamily of small G-proteins, cause Warburg Micro Syndrome (WARBM) which is characterized by defective neurodevelopmental and ophthalmological phenotypes. Despite loss of Rab18 had been reported to induce disruption of the endoplasmic reticulum structure and neuronal cytoskeleton organization, parts of the pathogenic mechanism caused by RAB18 mutation remain unclear. From the N-ethyl-N-nitrosourea (ENU)-induced mutagenesis library, we identified a mouse line whose Rab18 was knocked out...
May 2015: Experimental Neurology
Anna Kyunglim Park, Ryan P Liegel, Adam Ronchetti, Allison D Ebert, Aron Geurts, Duska J Sidjanin
BACKGROUND: Loss-of-function mutations in TBC1D20 cause Warburg Micro syndrome 4 (WARBM4), which is an autosomal recessive syndromic disorder characterized by eye, brain, and genital abnormalities. Blind sterile (bs) mice carry a Tbc1d20-null mutation and exhibit cataracts and testicular phenotypes similar to those observed in WARBM4 patients. In addition to TBC1D20, mutations in RAB3GAP1, RAB3GAP2 and RAB18 cause WARBM1-3 respectively. However, regardless of which gene harbors the causative mutation, all individuals affected with WARBM exhibit indistinguishable clinical presentations...
2014: BMC Genetics
Sylvie Picker-Minh, Andreas Busche, Britta Hartmann, Birgit Spors, Eva Klopocki, Christoph Hübner, Denise Horn, Angela M Kaindl
Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 (TBC1 domain protein, member 20) gene, respectively. Here, we delineate the so far largest intragenic homozygous RAB3GAP1 microdeletion. Despite the size of the RAB3GAP1 gene deletion, the patient phenotype is mainly consistent with that of other WARBM1 patients, supporting strongly the theory that WARBM1 is caused by a loss of RAB3GAP1 function...
2014: Orphanet Journal of Rare Diseases
Mark T Handley, André Mégarbané, Alison M Meynert, Stephen Brown, Elisabeth Freyer, Martin S Taylor, Ian J Jackson, Irene A Aligianis
Autosomal recessive cutis laxa type 3A is caused by mutations in ALDH18A1, a gene encoding the mitochondrial enzyme Δ(1)-pyrroline-5-carboxylate synthase (P5CS). It is a rare disorder with only six pathogenic mutations and 10 affected individuals from five families previously described in the literature. Here we report the identification of novel compound heterozygous missense mutations in two affected siblings from a Lebanese family by whole-exome sequencing. The mutations alter a conserved C-terminal domain of the encoded protein and reduce protein stability as determined through Western blot analysis of patient fibroblasts...
July 2014: Molecular Genetics & Genomic Medicine
Chih-Ya Cheng, Albert C Yang, Chu-Chung Huang, Mu-En Liu, Ying-Jay Liou, Jaw-Ching Wu, Shih-Jen Tsai, Ching-Po Lin, Chen-Jee Hong
Genetic factors are responsible for the development of the human brain. Certain genetic factors are known to increase the risk of common brain disorders and affect the brain structure. Therefore, even in healthy people, these factors have a role in the development of specific brain regions. Loss-of-function mutations in the RAB18 gene (RAB18) cause Warburg Micro syndrome, which is associated with reduced brain size and deformed brain structures. In this study, we hypothesized that the RAB18 variant might influence regional brain volumes in healthy people...
October 2014: Cerebellum
Andreas Gerondopoulos, Ricardo Nunes Bastos, Shin-Ichiro Yoshimura, Rachel Anderson, Sarah Carpanini, Irene Aligianis, Mark T Handley, Francis A Barr
The ancestral Rab GTPase Rab18 and both subunits of the Rab3GAP complex are mutated in the human neurological and developmental disorder Warburg Micro syndrome. Here, we demonstrate that the Rab3GAP complex is a specific Rab18 guanine nucleotide exchange factor (GEF). The Rab3GAP complex localizes to the endoplasmic reticulum (ER) and is necessary for ER targeting of Rab18. It is also sufficient to promote membrane recruitment of Rab18. Disease-associated point mutations of conserved residues in either the Rab3GAP1 (T18P and E24V) or Rab3GAP2 (R426C) subunits result in loss of the Rab18 GEF and membrane-targeting activities...
June 9, 2014: Journal of Cell Biology
Laurie E Seltzer, Alex R Paciorkowski
Several genetic disorders are characterized by normal head size at birth, followed by deceleration in head growth resulting in postnatal microcephaly. Among these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome). These disorders can be identified clinically by phenotyping across multiple neurodevelopmental and neurobehavioral realms, and enough data are available to recognize these postnatal microcephaly disorders as separate diagnostic entities in their own right...
June 2014: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
Sarah M Carpanini, Lisa McKie, Derek Thomson, Ann K Wright, Sarah L Gordon, Sarah L Roche, Mark T Handley, Harris Morrison, David Brownstein, Thomas M Wishart, Michael A Cousin, Thomas H Gillingwater, Irene A Aligianis, Ian J Jackson
Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18-mutant mouse model of WARBM...
June 2014: Disease Models & Mechanisms
Ryan P Liegel, Mark T Handley, Adam Ronchetti, Stephen Brown, Lars Langemeyer, Andrea Linford, Bo Chang, Deborah J Morris-Rosendahl, Sarah Carpanini, Renata Posmyk, Verity Harthill, Eamonn Sheridan, Ghada M H Abdel-Salam, Paulien A Terhal, Francesca Faravelli, Patrizia Accorsi, Lucio Giordano, Lorenzo Pinelli, Britta Hartmann, Allison D Ebert, Francis A Barr, Irene A Aligianis, Duska J Sidjanin
blind sterile (bs) is a spontaneous autosomal-recessive mouse mutation discovered more than 30 years ago. Phenotypically, bs mice exhibit nuclear cataracts and male infertility; genetic analyses assigned the bs locus to mouse chromosome 2. In this study, we first positionally cloned the bs locus and identified a putative causative mutation in the Tbc1d20 gene. Functional analysis established the mouse TBC1D20 protein as a GTPase-activating protein (GAP) for RAB1 and RAB2, and bs as a TBC1D20 loss-of-function mutation...
December 5, 2013: American Journal of Human Genetics
Mark T Handley, Deborah J Morris-Rosendahl, Stephen Brown, Fiona Macdonald, Carol Hardy, Danai Bem, Sarah M Carpanini, Guntram Borck, Loreto Martorell, Claudia Izzi, Francesca Faravelli, Patrizia Accorsi, Lorenzo Pinelli, Lina Basel-Vanagaite, Gabriela Peretz, Ghada M H Abdel-Salam, Maha S Zaki, Anna Jansen, David Mowat, Ian Glass, Helen Stewart, Grazia Mancini, Damien Lederer, Tony Roscioli, Fabienne Giuliano, Astrid S Plomp, Arndt Rolfs, John M Graham, Eva Seemanova, Pilar Poo, Angels García-Cazorla, Patrick Edery, Ian J Jackson, Eamonn R Maher, Irene A Aligianis
Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases...
May 2013: Human Mutation
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