TY  - JOUR
A1  - Krämer, Nadine
A1  - Ravindran, Ethiraj
A1  - Zaqout, Sami
A1  - Neubert, Gerda
A1  - Schindler, Detlev
A1  - Ninnemann, Olaf
A1  - Gräf, Ralph
A1  - Seiler, Andrea E. M.
A1  - Kaindl, Angela M.
T1  - Loss of CDK5RAP2 affects neural but not non-neural mESC differentiation into cardiomyocytes
JF  - Cell cycle
N2  - Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of Cdk5rap2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating Cdk5rap2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.
KW  - CDK5RAP2
KW  - MCPH
KW  - mental retardation
KW  - neural differentiation
KW  - primary microcephaly
KW  - stem cell
Y1  - 2015
U6  - https://doi.org/10.1080/15384101.2015.1044169
SN  - 1538-4101
SN  - 1551-4005
VL  - 14
IS  - 13
SP  - 2044
EP  - 2057
PB  - Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Hartmann, Bianca
A1  - Wai, Timothy
A1  - Hu, Hao
A1  - MacVicar, Thomas
A1  - Musante, Luciana
A1  - Fischer-Zirnsak, Björn
A1  - Stenzel, Werner
A1  - Gräf, Ralph
A1  - van den Heuvel, Lambert
A1  - Ropers, Hans-Hilger
A1  - Wienker, Thomas F.
A1  - Hübner, Christoph
A1  - Langer, Thomas
A1  - Kaindl, Angela M.
T1  - Homozygous YME1L1 Mutation Causes Mitochondriopathy with Optic Atrophy and Mitochondrial Network Fragmentation
JF  - eLife
N2  - Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.
KW  - YME1L1
KW  - mitochondriopathy
KW  - intellectual disability
KW  - optic atrophy
KW  - OPA1
KW  - mitochondrial fragmentation
Y1  - 2016
U6  - https://doi.org/10.7554/eLife.16078
SN  - 2050-084X
VL  - 5
SP  - 1156
EP  - 1165
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -