6533b873fe1ef96bd12d56cc
RESEARCH PRODUCT
Am J Hum Genet
Robert SmigielGéraldine Joly-helasLinyan MengGregory M. CooperNolwenn Jean-marçaisChristel Thauvin-robinetBruno KiefferChristopher T. GordonLaurence FaivreRhonda E. SchnurSarah L. DuganSeema R. LalaniHeather C MeffordSusan M. HiattMarlène RioSeiamak BahramJamel ChellyCaroline Schluth-bolardTatiana TvrdikAlison M. MuirEva ErdmannAline KolmerAurore GardeAngélique PichotRaphael CarapitoMary K. KukolichAndrea M. LewisDavid HuntClémantine DimartinoAurore MorlonAnne MolitorIngrid M. WentzensenFabien DutreuxNicodème PaulCarlos A. BacinoNina B. GoldFrédéric Tran Mau-themOlaf BodamerDeciphering Developmental Disorders StudyZijie SunPinar Bayrak-toydemirHeather P. CrawfordVictoria HarrisonJocelyn CéralineJeanne AmielMira KharbandaChristina HungA. HanauerAnne-marie GuerrotDavid ViskochilBertrand IsidorMaya ChopraKirsty McwalterLydie NaegelyMeredith PhillipsXia WangRafał PłoskiNoel Mensah-bonsuEkaterina L. IvanovaMagalie S. Leducsubject
0301 basic medicineMaleMicrocephaly[SDV]Life Sciences [q-bio]Developmental DisabilitiesAucunBiology030226 pharmacology & pharmacyTransactivation03 medical and health sciencesMiceNeurodevelopmental disorder0302 clinical medicineReportIntellectual DisabilityCoactivatormedicineGeneticsAnimalsHumansPoint MutationAlleleChildExomeGenetics (clinical)Alleles030304 developmental biologyGenetics0303 health sciencesPoint mutationCorrectionInfantSyndromemedicine.diseaseAndrogen receptor030104 developmental biologyChild PreschoolFemale030217 neurology & neurosurgeryTranscription Factorsdescription
ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-02-07 |