ABSTRACT
Contactin-associated protein-like 2 (CASPR2) is encoded by CNTNAP2 and clusters voltage-gated potassium channels (K(v)1.1) at the nodes of Ranvier. We report a homozygous mutation of CNTNAP2 in Old Order Amish children with cortical dysplasia, focal epilepsy, relative macrocephaly, and diminished deep-tendon reflexes. Intractable focal seizures began in early childhood, after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. Resective surgery did not prevent the recurrence of seizures. Temporal-lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2.
Subject(s)
Epilepsies, Partial/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Child , Child, Preschool , Electroencephalography , Epilepsies, Partial/pathology , Epilepsies, Partial/physiopathology , Epilepsies, Partial/surgery , Gene Expression , Homozygote , Humans , Magnetic Resonance Angiography , Membrane Proteins/metabolism , Mutation , Nerve Tissue Proteins/metabolism , Phenotype , Reflex, Stretch , Secondary Prevention , Seizures/etiology , Temporal Lobe/metabolism , Temporal Lobe/pathologyABSTRACT
We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation.
