TY - JOUR
T1 - MYT1L is a Candidate Gene for Intellectual Disability in Patients With 2p25.3 (2pter) Deletions
AU - Stevens, Servi J. C.
AU - van Ravenswaaij-Arts, Conny M. A.
AU - Janssen, Jannie W. H.
AU - Wassink-Ruiter, Jolien S. Klein
AU - van Essen, Anthonie J.
AU - Dijkhuizen, Trijnie
AU - van Rheenen, Jeroen
AU - Heuts-Vijgen, Regina
AU - Stegmann, Alexander P. A.
AU - Smeets, Eric E. J. G. L.
AU - Engelen, John J. M.
PY - 2011/11
Y1 - 2011/11
N2 - A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
AB - A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
KW - MYT1L
KW - intellectual disability
KW - SNP array
KW - array-CGH
KW - deletion 2p25.3 (2pter)
KW - neurogenesis
U2 - 10.1002/ajmg.a.34274
DO - 10.1002/ajmg.a.34274
M3 - Article
C2 - 21990140
SN - 1552-4825
VL - 155A
SP - 2739
EP - 2745
JO - American Journal of Medical Genetics Part A
JF - American Journal of Medical Genetics Part A
IS - 11
ER -