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'''ZTTK Syndromesyndrome (Zhu-Tokita-Takenouchi-Kim syndrome)''' is a rare multisystem disease caused in humans by a genetic mutation of the [[SON (gene)|SON gene]]. Common symptoms include moderate to severe [[intellectualDevelopmental disability|developmental delay]] and often light to severe [[developmentalintellectual delaydisability]].<ref name=":0">{{cite journal|doi=10.1016/j.ajhg.2016.06.029|pmid=27545680|pmc=5011044|title=De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome|journal=The American Journal of Human Genetics|volume=99|issue=3|pages=711–719|year=2016|last1=Kim|first1=Jung-Hyun|last2=Shinde|first2=Deepali N|last3=Reijnders|first3=Margot R.F|last4=Hauser|first4=Natalie S|last5=Belmonte|first5=Rebecca L|last6=Wilson|first6=Gregory R|last7=Bosch|first7=Daniëlle G.M|last8=Bubulya|first8=Paula A|last9=Shashi|first9=Vandana|last10=Petrovski|first10=Slavé|last11=Stone|first11=Joshua K|last12=Park|first12=Eun Young|last13=Veltman|first13=Joris A|last14=Sinnema|first14=Margje|last15=Stumpel|first15=Connie T.R.M|last16=Draaisma|first16=Jos M|last17=Nicolai|first17=Joost|last18=Yntema|first18=Helger G|last19=Lindstrom|first19=Kristin|last20=De Vries|first20=Bert B.A|last21=Jewett|first21=Tamison|last22=Santoro|first22=Stephanie L|last23=Vogt|first23=Julie|last24=Bachman|first24=Kristine K|last25=Seeley|first25=Andrea H|last26=Krokosky|first26=Alyson|last27=Turner|first27=Clesson|last28=Rohena|first28=Luis|last29=Hempel|first29=Maja|last30=Kortüm|first30=Fanny|display-authors=etal}}</ref><ref name="omim">{{cite web|title=OMIM Entry # 617140 - ZTTK SYNDROME; ZTTKS|url=http://omim.org/entry/617140|website=[[Online Mendelian Inheritance in Man]]|publisher=[[Johns Hopkins University]]|accessdateaccess-date=27 October 2017}}</ref>
Characteristic abnormalities include cerebral cortex malformations, vision difficulties, [[Musculoskeletal abnormality|musculoskeletal abnormalities]] and [[Birth defect|congenital defects]].<ref name=":0" /> Individuals with a mutation in the SON gene may not all display these features. However, SON loss of function (LoF) variants appear to cause a clinically distinguished phenotype.<ref name=":0" />
== Signs and Symptoms ==
The key signs and symptoms associated with ZTTK Syndrome patients include ocular, facial and systemic features.{{cncitation needed|date=November 2020}}
=== Ocular Features ===
=== Facial Features ===
Individuals with ZTTK syndrome have distinctive minor to moderate facial dysmorphisms. Distinct facial features include facial asymmetry, low-set ears, midface retraction, frontal bossing,<ref name=":2">{{Cite journal|lastlast1=Tokita|firstfirst1=Mari J.|last2=Braxton|first2=Alicia A.|last3=Shao|first3=Yunru|last4=Lewis|first4=Andrea M.|last5=Vincent|first5=Marie|last6=Küry|first6=Sébastien|last7=Besnard|first7=Thomas|last8=Isidor|first8=Bertrand|last9=Latypova|first9=Xénia|date=September 2016|title=De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive|journal=The American Journal of Human Genetics|volume=99|issue=3|pages=720–727|doi=10.1016/j.ajhg.2016.06.035|issn=0002-9297|pmc=5011061|pmid=27545676}}</ref> a depressed and or broad nasal bridge and a smooth or short philtrum.<ref name=":0" />
=== Systemic Features ===
=== Central Nervous System ===
Developmental delay is common in ZTTK syndrome patients, and appears to progressively increase the severity of intellectual disability with age.<ref name=":0" /> The development of gross and fine motor skills, as well as fluent and receptive language skills are shown to be delayed in developmental age. Macrocephaly and brain white matter abnormalities have also been observed.<ref name=":3">{{Cite journal|lastlast1=Zhu|firstfirst1=Xiaolin|last2=Petrovski|first2=Slavé|last3=Xie|first3=Pingxing|last4=Ruzzo|first4=Elizabeth K.|last5=Lu|first5=Yi-Fan|last6=McSweeney|first6=K. Melodi|last7=Ben-Zeev|first7=Bruria|last8=Nissenkorn|first8=Andreea|last9=Anikster|first9=Yair|date=2015-01-15|title=Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios|journal=Genetics in Medicine|volume=17|issue=10|pages=774–781|doi=10.1038/gim.2014.191|issn=1098-3600|pmc=4791490|pmid=25590979}}</ref> Seizures often develop between the ages of 1 toand 6 years old.<ref name=":1" />
=== Physiological ===
== Genetics ==
ZTTK syndrome is caused by heterozygous mutations in the SON gene.<ref name=":3" /> As an [[autosomal dominant]] disease, children with parents carrying a SON mutation have a 50% risk of inheriting the mutation. However, the majority of affected individuals have [[de novo mutationsmutation]]s in the SON gene and ZTTK syndrome is not inherited to their children.<ref name=":1" />
=== Allelic Variants of SON Gene ===
Many individuals with ZTTK syndrome have identified [[heterozygosity]] for a de novo 4-base pair deletion<ref name=":3" /><ref>{{Cite journal|lastlast1=Takenouchi|firstfirst1=Toshiki|last2=Miura|first2=Kiyokuni|last3=Uehara|first3=Tomoko|last4=Mizuno|first4=Seiji|last5=Kosaki|first5=Kenjiro|date=2016-06-03|title=EstablishingSONin 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype|journal=American Journal of Medical Genetics Part A|volume=170|issue=10|pages=2587–2590|doi=10.1002/ajmg.a.37761|pmid=27256762|issn=1552-4825|doi-access=free}}</ref><sup>,</sup> de novo mutation in [[exon]] 3 in the SON gene<ref name=":0" /> and de novo 2-base point insertion in exon,<ref name=":0" /> resulting in [[haploinsufficiency]] or a frameshift and premature termination in the [[arginine]]/[[serine]] (RS) domain. Peripheral blood cells from the sampled patients confirmed decreased levels of the mutant RNA transcript, consistent with haploinsufficiency.<ref name=":0" /> Other mutations observed include a [[nonsense mutation]], an [[in-frame deletion]] of amino acids and an entire gene deletion.<ref name=":0" /> De novo heterozygous 1-base point duplication in exon 3 and 1-base point deletion in exon 4 of the SON gene resulted in a frameshift and premature termination.<ref name=":2" /> Parental DNA has confirmed that de novo mutations are common in patients with ZTTK syndrome.<ref name=":0" /> De novo LoF mutations and haploinsufficiency for the SON gene are shown to cause profound developmental malformations during [[embryonic development]] as seen in the phenotypic manifestations of the ZTTK syndrome.<ref name=":2" />
=== Structure of SON Gene ===
SON is a large protein consisting of 2426 amino acids and repeat sequences.<ref name=":4">{{Cite journal|lastlast1=Ahn|firstfirst1=Eun-Young|last2=DeKelver|first2=Russell C.|last3=Lo|first3=Miao-Chia|last4=Nguyen|first4=Tuyet Ann|last5=Matsuura|first5=Shinobu|last6=Boyapati|first6=Anita|last7=Pandit|first7=Shatakshi|last8=Fu|first8=Xiang-Dong|last9=Zhang|first9=Dong-Er|date=April 2011|title=SON Controls Cell-Cycle Progression by Coordinated Regulation of RNA Splicing|journal=Molecular Cell|volume=42|issue=2|pages=185–198|doi=10.1016/j.molcel.2011.03.014|issn=1097-2765|pmid=21504830|pmc=3137374}}</ref> SON is located within the human chromosomal region 21q22.11 in nuclear speckles and consists of 12 exons.<ref>{{Cite journal|lastlast1=Khan|firstfirst1=I. M.|last2=Fisher|first2=R. A.|last3=Johnson|first3=K. J.|last4=Bailey|first4=M. E. S.|last5=Siciliano|first5=M. J.|last6=Kessling|first6=A. M.|last7=Farrer|first7=M.|last8=Carritt|first8=B.|last9=Kamalati|first9=T.|date=January 1994|title=The SON gene encodes a conserved DNA binding protein mapping to human chromosome 21|journal=Annals of Human Genetics|volume=58|issue=1|pages=25–34|doi=10.1111/j.1469-1809.1994.tb00723.x|pmid=8031013|s2cid=31519119|issn=0003-4800}}</ref> Exon 3 of the SON gene is particularly large, accounting for 82% of the entire coding region.<ref name=":0" /> The majority of SON variants found in ZTTK syndrome individuals are localised to exon 3.<ref name=":2" />
== Mechanism ==
[[File:Role_of_SON_in_ZTTK_SyndromeRole of SON in ZTTK Syndrome.png|thumb|Role of the spliceosome-associated gene, SON in regulating RNA splicing through intron retention and exon skipping to maintain the pluripotency of human embryonic stem cells (hESCs) and cell-cycle progression.]]
=== Role of SON in RNA Splicing ===
The [[SON (gene)|SON gene]] encodes the SON protein, which is able to bind to DNA and RNA.<ref name=":5">{{Cite journal|lastlast1=Lu|firstfirst1=Xinyi|last2=Ng|first2=Huck-Hui|last3=Bubulya|first3=Paula A.|date=2014-04-30|title=The role of SON in splicing, development, and disease|journal=Wiley Interdisciplinary Reviews: RNA|volume=5|issue=5|pages=637–646|doi=10.1002/wrna.1235|issn=1757-7004|pmc=4138235|pmid=24789761}}</ref> The SON protein is mainly localised to [[nuclear specklesspeckle]]s and involved in a variety of cellular processes such as transcription, cell cycle regulation and subnuclear organisation of pre-messenger RNA (mRNA) splicing.<ref name=":5" /><ref>{{Cite journal|lastlast1=Spector|firstfirst1=D. L.|last2=Lamond|first2=A. I.|date=2010-10-06|title=Nuclear Speckles|journal=Cold Spring Harbor Perspectives in Biology|volume=3|issue=2|pages=a000646|doi=10.1101/cshperspect.a000646|issn=1943-0264|pmid=20926517|pmc=3039535}}</ref>
SON contains various domains such as the RS-rich domain, a G-patch domain and a double-stranded RNA-binding motif.<ref name=":4" /><ref>{{Cite journal|lastlast1=Hickey|firstfirst1=Christopher J.|last2=Kim|first2=Jung-Hyun|last3=Ahn|first3=Eun-Young Erin|date=2013-12-13|title=New Discoveries of Old SON: A Link Between RNA Splicing and Cancer|journal=Journal of Cellular Biochemistry|volume=115|issue=2|pages=224–231|doi=10.1002/jcb.24672|pmid=24030980|s2cid=23130360|issn=0730-2312}}</ref> The presence of these domains is necessary for SON to mediate constitutive and alternative splicing.<ref name=":0" /> The RS-rich domain serves to localise SON in nuclear speckles with pre-mRNA processing factors.<ref name=":5" /> The functional domains and specific localisation of SON in nuclear speckles has indicated its role in pre-mRNA splicing.<ref name=":5" />
SON also plays a key role in [[alternative splicing]] of exons. SON is required for genome stability by ensuring the efficiency of RNA splicing of weak constitutive and alternative splice sites. SON-dependent cell-cycle genes possess a weak 5’ or 3’ splice site and are dependent on SON to ensure efficient splicing and spliceosome recognition.<ref name=":4" />
The SON gene also plays a critical role during development. SON is expressed preferentially in undifferentiated stem cells.<ref name=":5" /> Depletion of SON results in stem cell differentiation.<ref name=":5" />
[[Human embryonic stem cells]] (hESCs) are able to undergo lineage-specific differentiation into specific types of cells, known as [[pluripotency]].<ref name=":6">{{Cite journal|lastlast1=Lu|firstfirst1=Xinyi|last2=Göke|first2=Jonathan|last3=Sachs|first3=Friedrich|last4=Jacques|first4=Pierre-Étienne|last5=Liang|first5=Hongqing|last6=Feng|first6=Bo|last7=Bourque|first7=Guillaume|last8=Bubulya|first8=Paula A.|last9=Ng|first9=Huck-Hui|date=2013-09-08|title=SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells|journal=Nature Cell Biology|volume=15|issue=10|pages=1141–1152|doi=10.1038/ncb2839|issn=1465-7392|pmc=4097007|pmid=24013217}}</ref> Pluripotent stem cells, such as hESCs can undergo [[gastrulation]] to give rise to the three germ layers.<ref name=":5" />
A significant level of SON expression in fetal tissue has suggested a regulatory role of SON in cellular proliferation and or differentiation during embryonic development by influencing the splicing of pluripotency maintenance genes.<ref>{{Cite journal|lastlast1=Cheng|firstfirst1=Suzanne|last2=Lutfalla|first2=Georges|last3=Uze|first3=Gilles|last4=Chumakov|first4=Ilya M.|last5=Gardiner|first5=Katheleen|date=1993|title=GART, SON, IFNAR, and CRF2-4 genes cluster on human Chromosome 21 and mouse Chromosome 16|journal=Mammalian Genome|volume=4|issue=6|pages=338–342|doi=10.1007/bf00357094|pmid=8318737|s2cid=19770065|issn=0938-8990}}</ref> The expression of [[transcription factor]]s such as the SON factor and epigenetic modifiers regulate the pluripotency of hESCs by ensuring genes undergo RNA splicing to create a mature RNA transcript.<ref name=":7">{{Cite journal|lastlast1=Livyatan|firstfirst1=Ilana|last2=Meshorer|first2=Eran|date=October 2013|title=SON sheds light on RNA splicing and pluripotency|journal=Nature Cell Biology|volume=15|issue=10|pages=1139–1140|doi=10.1038/ncb2851|issn=1465-7392|pmid=24084863|s2cid=12137904}}</ref>
The SON gene is required for RNA splicing of transcripts encoding the cell-cycle protein TUBG1 and genes maintaining hESC pluripotency; PRDM14, OCTA, E4F1 and MED24 in hESCs.<ref name=":6" /> As OCT4 is involved in the core transcriptional circuitry in hESCs, misregulation of OCT4 induces cell differentiation. PRDM14 is a pluripotency regulator and MED24 is a mediator complex essential in the maintenance of pluripotency.<ref name=":6" /> In wild-type ESCs, SON binding to the RNA transcripts of pluripotency regulating genes such as PRDM14 and OCT4 results in correct splicing and maintenance of pluripotency.<ref name=":7" />
=== Effects of SON Haploinsufficiency on RNA Splicing and Embryonic Development ===
The downregulation of SON can impact the regulation of mitotic regulator transcripts and cause defects in cell survival and the developmental process.<ref name=":5" /> SON depletion causes decreased cell growth,<ref name=":4" /><ref name=":8">{{Cite journal|lastlast1=Huen|firstfirst1=Michael S.Y.|last2=Sy|first2=Shirley M.H.|last3=Leung|first3=Ka Man|last4=Ching|first4=Yick-Pang|last5=Tipoe|first5=George L.|last6=Man|first6=Cornelia|last7=Dong|first7=Shuo|last8=Chen|first8=Junjie|date=July 2010|title=SON is a spliceosome-associated factor required for mitotic progression|journal=Cell Cycle|volume=9|issue=13|pages=2679–2685|doi=10.4161/cc.9.13.12151|pmid=20581448|pmc=3040851|issn=1538-4101}}</ref><ref name=":9">{{Cite journal|lastlast1=Sharma|firstfirst1=Alok|last2=Takata|first2=Hideaki|last3=Shibahara|first3=Kei-ichi|last4=Bubulya|first4=Athanasios|last5=Bubulya|first5=Paula A.|date=2010-02-15|title=Son Is Essential for Nuclear Speckle Organization and Cell Cycle Progression|journal=Molecular Biology of the Cell|volume=21|issue=4|pages=650–663|doi=10.1091/mbc.e09-02-0126|issn=1059-1524|pmc=2820428|pmid=20053686}}</ref> disarrayed microtubule processes and disordered spindle pole separation, causing mitotic arrest at [[metaphase]] and severe genome integrity impairment.<ref name=":4" /><ref name=":8" /><ref name=":9" /> Mitotic cells without functional SON have increased double-stranded DNA breaks and micronuclei formation.<ref name=":8" /> Consequently, genome stability and regulation of the cell cycle are compromised, contributing to the development of multi-organ defects in ZTTK syndrome patients.<ref name=":4" />
Aberrant splicing and de novo heterozygous LoF mutations in SON gene disrupts the process of gene expression and can result in SON haploinsufficiency.<ref>{{Cite journal|lastlast1=Cooper|firstfirst1=Thomas A.|last2=Wan|first2=Lili|last3=Dreyfuss|first3=Gideon|date=February 2009|title=RNA and Disease|journal=Cell|volume=136|issue=4|pages=777–793|doi=10.1016/j.cell.2009.02.011|pmid=19239895|pmc=2866189|issn=0092-8674}}</ref><ref name=":3" /> ZTTK syndrome individuals with SON haploinsufficiency display decreased mRNA expression and abnormal RNA splicing products of numerous genes which are necessary for neuronal cell migration, metabolic processes and neurodevelopment of the brain.<ref name=":3" />
RNA analyses from affected individuals with ZTTK syndrome confirmed the downregulation of genes essential for neuronal migration and cortex organisation ([[TUBG1]], [[FLNA]], [[PNKP]], [[WDR62]], [[PSMD3]], [[HDAC6]]) and metabolism ([[PCK2]], [[PFKL]], [[IDH2]], [[ACY1]], and [[Adenosine deaminase|ADA]]).<ref name=":0" /> Aberrant SON-mediated RNA splicing results from the accumulation of mis-spliced transcripts.<ref name=":0" /> The mis-spliced RNA products are caused by significant intron retention (TUBG1, FLNA, PNKP, WDR62, PSMD3, PCK2, PFKL, IDH2, and ACY1) and exon skipping (HDAC6 and ADA).<ref name=":0" /> In contrast, the parents of individuals with ZTTK syndrome display an absence of mis-spliced RNA products.<ref name=":0" />
SON depletion downregulates and causes aberrant splicing of the pluripotency factors, [[Oct-4|OCT4]], [[PRDM16|PRDM14]], [[MED24]] and [[E4F1]], inducing spontaneous differentiation of hESCs followed by widespread cell death.<ref name=":6" /><ref name=":7" /> As SON acts as an [[intron splicing]] activator, the depletion of SON leads to increased intron retention and [[exon skipping]] in hESCs in regulatory genes of the cell cycle and hESC identity.<ref>{{Cite journal|lastlast1=Juan-Mateu|firstfirst1=Jonàs|last2=Villate|first2=Olatz|last3=Eizirik|first3=Décio L|date=May 2016|title=MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research|journal=European Journal of Endocrinology|volume=174|issue=5|pages=R225–R238|doi=10.1530/eje-15-0916|pmid=26628584|issn=0804-4643|doi-access=free|pmc=5331159}}</ref> Mutations in the SON gene and or SON haploinsufficiency compromises SON-mediated RNA splicing and contributes to the complex developmental defects observed in individuals with ZTTK syndrome.<ref name=":0" /> Erroneous SON function causes insufficient production of downstream targets, genome instability and disrupted cell cycle progression which are fundamental to the developmental defects and organ abnormalities in individuals with ZTTK syndrome. For example, FLNA haploinsufficiency observed in individuals with ZTTK syndrome is the main cause of a rare brain disorder, [[Periventricular Nodular Heterotopia|periventricular nodular heterotopia]]. De novo LoF mutations in TUBG1 can result in [[microcephaly]] and cortical malformations due to compromised SON-mediated RNA splicing in affected ZTTK syndrome individuals.<ref>{{Cite journal|lastlast1=Poirier|firstfirst1=Karine|last2=Lebrun|first2=Nicolas|last3=Broix|first3=Loic|last4=Tian|first4=Guoling|last5=Saillour|first5=Yoann|last6=Boscheron|first6=Cécile|last7=Parrini|first7=Elena|last8=Valence|first8=Stephanie|last9=Pierre|first9=Benjamin Saint|date=2013-04-21|title=Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly|journal=Nature Genetics|volume=45|issue=6|pages=639–647|doi=10.1038/ng.2613|issn=1061-4036|pmc=3826256|pmid=23603762}}</ref>
The consequence of SON haploinsufficiency on embryonic development has also been studied in zebrafish animal models (''Danio rerio).'' A range of developmental defects was observed, including bent, shortened or gnarled tails, massive body curvatures with deformed body axes, eye malformations and microcephaly.<ref name=":0" /> Embryos that survived for a longer period of time have more severe phenotypes such as spinal malformations with brain oedema, imitating features observed in affected ZTTK syndrome individuals.<ref name=":0" />
Other pathological features seen on MRI scans of ZTTK syndrome individuals include [[arachnoid cyst]]s, [[hypoplasia of the corpus callosum]] and cerebellar hemispheres and loss of periventricular white matter.<ref name=":0" />
Most individuals with ZTTK syndrome are identified early in childhood due to developmental delays and intellectual disabilities.<ref name=":11">{{Cite journal|lastlast1=Vissers|firstfirst1=Lisenka E. L. M.|last2=Gilissen|first2=Christian|last3=Veltman|first3=Joris A.|date=2015-10-27|title=Genetic studies in intellectual disability and related disorders|journal=Nature Reviews Genetics|volume=17|issue=1|pages=9–18|doi=10.1038/nrg3999|pmid=26503795|s2cid=16723395|issn=1471-0056}}</ref> However, a formal diagnosis of intellectual disability can only be conducted by a performance of an IQ test score of below 70.<ref name=":10" />
=== Whole Exome Sequencing ===
[[Whole exome sequencing]] (WES) can be used as a non-biased tool in the diagnostic evaluation of individuals with suspected genetic disorders such as the ZTTK syndrome.<ref name=":0" /> Using WES, individuals were identified with truncating variants of SON and overlapping clinical features.{{cncitation needed|date=November 2020}}
ZTTK syndrome has been identified as a neurodevelopmental disorder associated with a de novo mutation in the SON gene using WES. The SON gene is known to be a major cause of severe intellectual disability and consequent developmental disorders.<ref name=":11" /> The first de novo truncating variant in SON was recognised in a group of individuals with severe intellectual disabilities.<ref name=":3" /> Sanger sequencing or the use of WES of parental samples confirmed the de novo status of the truncating and missense mutations of the SON gene in the sampled ZTTK syndrome individuals.<ref name=":0" /> Variants identified included a premature stop variant in exon 3, frame-shift variants in exon 3 and a frameshift variant in exon 4.<ref name=":0" />
== Treatment ==
There is currently no treatment for ZTTK syndrome. However, physical therapy and addressing the specific problems of multi organ disorders may be helpful.<ref name=":1" /> The main focus should be on the diagnosis and care of individuals with ZTTK syndrome.{{cn}}
== Research ==
As of 2024, a patient group is attempting to raise money to research a cure involving gene therapy or gene editing.<ref>{{cite news |url=https://www.bostonglobe.com/2024/02/28/business/somerville-rare-disease-zttk-syndrome/ |title=A Somerville boy has one of the world’s rarest diseases. His parents are determined to find a cure. |author=Jonathan Saltzman |date=February 28, 2024 |newspaper=[[The Boston Globe]]}}</ref>
== References ==
{{Reflist}}
[[Category:Rare genetic syndromes]]
[[Category:GeneticSyndromes syndromeswith intellectual disability]]
[[Category:Syndromes with mental retardation]]
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