De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

American Journal of Human Genetics
Maja HempelDavor Lessel

Abstract

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.

References

Sep 7, 2002·Mental Retardation and Developmental Disabilities Research Reviews·Helen Leonard, Xingyan Wen
Sep 25, 2007·Journal of Child Neurology·Eboni I LanceKenton R Holden
Apr 14, 2009·American Journal of Medical Genetics. Part a·Maria KirchhoffMargarita Stefanova
Oct 5, 2012·The New England Journal of Medicine·Joep de LigtLisenka E L M Vissers
Aug 31, 2013·PLoS Genetics·Slavé PetrovskiDavid B Goldstein
May 9, 2014·Journal of Medical Genetics·Marjolein H WillemsenTjitske Kleefstra
Nov 18, 2014·Indian Journal of Human Genetics·Eiman BagherizadehFarkhondeh Behjati

❮ Previous
Next ❯

Citations

May 24, 2016·Molecular Genetics and Metabolism·Vera Uliana, Antonio Percesepe
Jul 29, 2016·Molecular Genetics & Genomic Medicine·Nara L Sobreira, David Valle
Jul 21, 2016·European Journal of Human Genetics : EJHG·Johanna SchäfgenHartmut Engels
Jun 14, 2017·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jacob J Michaelson
Sep 22, 2017·International Journal of Molecular Sciences·Sara Anna BoniniMaurizio Memo
Sep 9, 2017·American Journal of Medical Genetics. Part a·Edith SaidDavor Lessel
Feb 18, 2020·American Journal of Medical Genetics. Part a·Isabelle C WindheuserHartmut Engels
Mar 24, 2020·Journal of Neurochemistry·Fatemeh Hassani NiaHans-Jürgen Kreienkamp
May 1, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kamal KhanJuliane Winkelmann
Feb 27, 2016·Genome Medicine·Holly A F StessmanEvan E Eichler
Jul 10, 2020·The Journal of Obstetrics and Gynaecology Research·Tong LiuJingfang Zhai
Sep 26, 2017·Molecular Genetics & Genomic Medicine·Nobuhiko OkamotoNaomichi Matsumoto
Dec 14, 2019·Brain : a Journal of Neurology·Christopher C Y MakChristopher T Gordon
Dec 19, 2018·Cold Spring Harbor Molecular Case Studies·Brooke McKennaJacob J Michaelson
Dec 24, 2018·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Kimberly A AldingerDan Doherty
Apr 10, 2019·Human Genetics·Katja KlothKerstin Kutsche
May 6, 2019·Deutsches Ärzteblatt International·Elisa A MahlerMaja Hempel
Nov 18, 2020·Nature Communications·Davor LesselHans-Jürgen Kreienkamp
Jul 3, 2021·International Journal of Molecular Sciences·Carla LiaciGiorgio R Merlo
May 23, 2021·Cold Spring Harbor Molecular Case Studies·Madison GarrityWendy K Chung
Aug 19, 2021·Human Genome Variation·Yuta AsakuraTakanori Yamagata
Oct 15, 2021·European Journal of Human Genetics : EJHG·Oliver MurchAndrew E Fry

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.