Two New Cases of Primary Microcephaly with Neuronal Migration Defect Caused by Truncating Mutations in the ASPM Gene

Autosomal recessive primary microcephaly (MCPH) is a uncommon disorder due to congenital deficiency in the development of the cerebral cortex, characterized by a head circumference below 2 SD. MCPH is a group of diseases with genetic heterogeneity and has been reported by the Online Mendelian Inheritance In Man® (OMIM) database and associated with 25 different genes. It is known that MCPH cases are most frequently associated with abnormal spindle-like, microcephaly-associated (<i>ASPM</i>) gene mutations. The ASPM protein consists of an N-terminal 81 IQ (isoleucine-glutamine) domain, a calponin-homology domain, and a C-terminal domain. It interacts with calmodulin and calmodulin-related proteins via the IQ domain and acts as a part in mitotic spindle function. The basic characteristics of cases with <i>ASPM</i> gene mutations are microcephaly (below <b>−</b>3 SD) present before 1 year of age, intellectual disability, and the absence of other congenital anomalies. Macroscopic organization of the brain is preserved in cases with <i>ASPM</i> mutation, and a decrease in brain volume, particularly gray matter volume loss and a simplified gyral pattern are observed. Cortical migration defects are a very rare finding in patients with <i>ASPM</i> mutations. In the present study, we aimed to discuss the clinical and genetic findings in 2 cases with cortical dysplasia in which truncated variants in the <i>ASPM</i> gene were detected, particularly in terms of genotype-phenotype correlation in comparison with the literature.

Pex13 Inactivation in the Mouse Disrupts Peroxisome Biogenesis and Leads to a Zellweger Syndrome Phenotype

ABSTRACT Zellweger syndrome is the archetypical peroxisome biogenesis disorder and is characterized by defective import of proteins into the peroxisome, leading to peroxisomal metabolic dysfunction and widespread tissue pathology. In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype. To develop mouse models for this disorder, we have generated a targeted mouse with a loxP-modified Pex13 gene to enable conditional Cre recombinase-mediated inactivation of Pex13. In the studies reported here, we crossed these mice with transgenic mice that express Cre recombinase in all cells to generate progeny with ubiquitous disruption of Pex13. The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals. Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect. Thus, Pex13−/− mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans.