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Phelan-McDermid Syndrome

Reinhard Roessler, Johanna Goldmann, Chikdu Shivalila, Rudolf Jaenisch
Phelan-McDermid syndrome (also known as 22q13.3 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3 . However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 ( MAPK8IP2 ) may contribute to a distinct neurodevelopmental phenotype in neural progenitor cells (NPCs) affecting neuronal maturation...
August 2018: Life science alliance
Chantelle Fourie, Yukti Vyas, Kevin Lee, Yewon Jung, Craig C Garner, Johanna M Montgomery
The SHANK family of synaptic proteins (SHANK1-3) are master regulators of the organizational structure of excitatory synapses in the brain. Mutations in SHANK1-3 are prevalent in patients with autism spectrum disorders (ASD), and loss of one copy of SHANK3 causes Phelan-McDermid Syndrome, a syndrome in which Autism occurs in >80% of cases. The synaptic stability of SHANK3 is highly regulated by zinc, driving the formation of postsynaptic protein complexes and increases in excitatory synaptic strength. As ASD-associated SHANK3 mutations retain responsiveness to zinc, here we investigated how increasing levels of dietary zinc could alter behavioral and synaptic deficits that occur with ASD...
2018: Frontiers in Cellular Neuroscience
Siddharth Srivastava, Benoit Scherrer, Anna K Prohl, Rajna Filip-Dhima, Kush Kapur, Alexander Kolevzon, Joseph D Buxbaum, Elizabeth Berry-Kravis, Latha Soorya, Audrey Thurm, Craig M Powell, Jonathan A Bernstein, Simon K Warfield, Mustafa Sahin
OBJECTIVE: Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients. METHODS: We performed volumetric analysis on baseline brain MRIs of Phelan-McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials...
September 21, 2018: Pediatric Neurology
Petra Jungová, Andrea Čumová, Veronika Kramarová, Jana Lisyová, Pavol Ďurina, Ján Chandoga, Daniel Bӧhmer
Phelan-McDermid syndrome (PMD) is a rare genetic condition with only a few cases describing patients diagnosed as adults. We describe a long diagnostic odyssey of a 30-year-old woman who was diagnosed with Phelan-McDermid syndrom. Array comparative genomic hybridization analysis confirmed a 22q13.33 deletion, encompassing exon 9-23 of the SHANK3 gene and exon 1 of the ACR gene. We provide an uncommon feature of the disease, where psychotic alteration is repeatedly triggered by the same physical factor in our patient - mild fever episodes...
October 30, 2018: Neurocase
Dawn Adams, Richard P Hastings, Clair Alston-Knox, Rina Cianfaglione, Kate Eden, David Felce, Gemma Griffith, Jo Moss, Chris Stinton, Chris Oliver
BACKGROUND: It is well documented that mothers of children with intellectual disabilities or autism experience elevated stress, with mental health compromised. However, comparatively little is known about mothers of children with rare genetic syndromes. This study describes mental health and well-being in mothers of children with 13 rare genetic syndromes and contrasts the results with mothers of children with autism. METHODS: Mothers of children with 13 genetic syndromes (n = 646; Angelman, Cornelia de Lange, Down, Fragile-X, Phelan McDermid, Prader-Willi, Rett, Rubenstein Taybi, Smith Magenis, Soto, Tuberous Sclerosis Complex, 1p36 deletion and 8p23 deletion syndromes) and mothers of children with autism (n = 66) completed measures of positive mental health, stress and depression...
October 25, 2018: Orphanet Journal of Rare Diseases
Taesun Yoo, Heejin Cho, Jiseok Lee, Haram Park, Ye-Eun Yoo, Esther Yang, Jin Yong Kim, Hyun Kim, Eunjoon Kim
Shank3 is an excitatory postsynaptic scaffolding protein implicated in multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). Although previous neurobiological studies on Shank3 and Shank3 -mutant mice have revealed diverse roles of Shank3 in the regulation of synaptic, neuronal and brain functions, whether Shank3 expression in specific cell types distinctly contributes to mouse phenotypes remains largely unclear. In the present study, we generated two Shank3 -mutant mouse lines (exons 14-16) carrying global and GABA neuron-specific deletions and characterized their electrophysiological and behavioral phenotypes...
2018: Frontiers in Cellular Neuroscience
Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D Buxbaum
Phelan-McDermid syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability (ID), and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms...
May 2018: ENeuro
Jariya Upadia, Patrick R Gonzales, T Prescott Atkinson, Harry W Schroeder, Nathaniel H Robin, Natasha L Rudy, Fady M Mikhail
Phelan-McDermid syndrome (PMS, OMIM 606232) is a heterozygous contiguous gene microdeletion syndrome occurring at the distal region of chromosome 22q13. This deletion encompasses the SHANK3 gene at 22q13.33, which is thought to be the critical gene for the neurodevelopmental features seen in this syndrome. PMS is typically characterized by intellectual disability, autism spectrum disorder, absent to severely delayed speech, neonatal hypotonia, and dysmorphic features. Two patients presenting with classic clinical features of PMS have been reported to have interstitial microdeletions in the 22q13...
September 14, 2018: American Journal of Medical Genetics. Part A
Nhan Thi Ho, Barbara Kroner, Zachary Grinspan, Brandy Fureman, Kathleen Farrell, Jingzhou Zhang, Janice Buelow, Dale C Hesdorffer
OBJECTIVE: To describe the prevalence and characteristics of comorbidities in persons with rare epilepsies. STUDY DESIGN: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities...
September 5, 2018: Journal of Pediatrics
Tommy Hu, Paul Kruszka, Ariel F Martinez, Jeffrey E Ming, Emily K Shabason, Manu S Raam, Tamim H Shaikh, Daniel E Pineda-Alvarez, Maximilian Muenke
Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. The karyotype approach initially demonstrated several recurrent chromosomal anomalies, which led to the identification of HPE-specific loci and, eventually, several major HPE genes...
June 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
Jana Braesel, Camila M Crnkovic, Kevin J Kunstman, Stefan J Green, Mark Maienschein-Cline, Jimmy Orjala, Brian T Murphy, Alessandra S Eustáquio
Actinomycete bacteria isolated from freshwater environments are an unexplored source of natural products. Here we report the complete genome of the Great Lakes-derived Micromonospora sp. strain B006, revealing its potential for natural product biosynthesis. The 7-megabase pair chromosome of strain B006 was sequenced using Illumina and Oxford Nanopore technologies followed by Sanger sequencing to close remaining gaps. All identified biosynthetic gene clusters (BGCs) were manually curated. Five known BGCs were identified encoding desferrioxamine, alkyl- O-dihydrogeranylmethoxyhydroquinone, a spore pigment, sioxanthin, and diazepinomicin, which is currently in phase II clinical trials to treat Phelan-McDermid syndrome and co-morbid epilepsy...
September 28, 2018: Journal of Natural Products
Ponson Laura, Gomot Marie, Blanc Romuald, Barthelemy Catherine, Roux Sylvie, Munnich Arnold, Romana Serge, Aguillon-Hernandez Nadia, Malan Valérie, Bonnet-Brilhault Frédérique
Phelan-McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype-phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments...
August 8, 2018: Translational Psychiatry
Samuel E Taylor, Ruth D Taylor, Jack Price, Laura C Andreae
BACKGROUND: Deletions and mutations in the SHANK3 gene are strongly associated with autism spectrum disorder and underlie the autism-associated disorder Phelan-McDermid syndrome. SHANK3 is a scaffolding protein found at the post-synaptic membrane of excitatory neurons. METHODS: Single-molecule fluorescence in-situ hybridization (smFISH) allows the visualization of single mRNA transcripts in vitro. Here we perform and quantify smFISH in human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting the SHANK3 transcript...
July 31, 2018: Stem Cell Research & Therapy
Haitham Amal, Boaz Barak, Vadiraja Bhat, Guanyu Gong, Brian A Joughin, John S Wishnok, Guoping Feng, Steven R Tannenbaum
Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO• )-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions...
July 9, 2018: Molecular Psychiatry
Joerg Kallen, Christian Bergsdorf, Bertrand Arnaud, Mario Bernhard, Murielle Brichet, Amanda Cobos-Correa, Azeddine Elhajouji, Felix Freuler, Ivan Galimberti, Christel Guibourdenche, Simon Haenni, Sandra Holzinger, Juerg Hunziker, Aude Izaac, Markus Kaufmann, Lukas Leder, Hans-Joerg Martus, Peter von Matt, Valery Polyakov, Patrik Roethlisberger, Guglielmo Roma, Nikolaus Stiefl, Marianne Uteng, Andreas Lerchner
CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e...
July 9, 2018: ChemMedChem
Simone Hagmeyer, Ann Katrin Sauer, Andreas M Grabrucker
The loss of one copy of SHANK3 (SH3 and multiple ankyrin repeat domains 3) in humans highly contributes to Phelan McDermid syndrome (PMDS). In addition, SHANK3 was identified as a major autism candidate gene. Interestingly, the protein encoded by the SHANK3 gene is regulated by zinc. While zinc deficiency depletes synaptic pools of Shank3, increased zinc levels were shown to promote synaptic scaffold formation. Therefore, the hypothesis arises that patients with PMDS and Autism caused by Shankopathies, having one intact copy of SHANK3 left, may benefit from zinc supplementation, as elevated zinc may drive remaining Shank3 into the post-synaptic density (PSD) and may additional recruit Shank2, a second zinc-dependent member of the SHANK gene family...
2018: Frontiers in Synaptic Neuroscience
Anna A Kashevarova, Elena O Belyaeva, Aleksandr M Nikonov, Olga V Plotnikova, Nikolay A Skryabin, Tatyana V Nikitina, Stanislav A Vasilyev, Yulia S Yakovleva, Nadezda P Babushkina, Ekaterina N Tolmacheva, Mariya E Lopatkina, Renata R Savchenko, Lyudmila P Nazarenko, Igor N Lebedev
Background: Ring chromosome instability may influence a patient's phenotype and challenge its interpretation. Results: Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13...
2018: Molecular Cytogenetics
Meghan Kerrisk Campbell, Morgan Sheng
Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). Loss of SHANK3 in mouse models results in decreased synapse density and reduction in the levels of multiple synaptic proteins (Jiang and Ehlers, 2013). The family of SHANK scaffolding molecules are among the most heavily ubiquitinated proteins at the postsynaptic density. The ubiquitin-dependent proteasome degradation of SHANK is regulated by synaptic activity and may contribute to activity-dependent synaptic remodeling (Ehlers, 2003; Shin et al...
June 6, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Silvia De Rubeis, Paige M Siper, Allison Durkin, Jordana Weissman, François Muratet, Danielle Halpern, Maria Del Pilar Trelles, Yitzchak Frank, Reymundo Lozano, A Ting Wang, J Lloyd Holder, Catalina Betancur, Joseph D Buxbaum, Alexander Kolevzon
Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking...
2018: Molecular Autism
Wenmiao Zhu, Jianli Li, Stella Chen, Jinglan Zhang, Francesco Vetrini, Alicia Braxton, Christine M Eng, Yaping Yang, Fan Xia, Kory L Keller, Leila Okinaka-Hu, Chung Lee, J Lloyd Holder, Weimin Bi
SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias...
April 2018: American Journal of Medical Genetics. Part A
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