👤 Roderick Bronson

Juvenile-onset neuronal ceroid lipofuscinosis (JNCL; Batten disease) features hallmark membrane deposits and loss of central nervous system (CNS) neurons. Most cases of the disease are due to recessive inheritance of an approximately 1 kb deletion in the CLN3 gene, encoding battenin. To investigate the common JNCL mutation, we have introduced an identical genomic DNA deletion into the murine CLN3 homologue (Cln3) to create Cln3( Deltaex7/8) knock-in mice. The Cln3( Deltaex7/8) allele produced alternatively spliced mRNAs, including a variant predicting non-truncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3( Deltaex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. However, liver enzymes and CNS development were normal. Instead, Cln3( Deltaex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex and cerebellum, as well as neurological deficits and premature death. Thus, the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons. Show less

Ventricular septal defects are common in human infants, but the genetic programs that control ventricular septation are poorly understood. Here we report that mice with a targeted disruption of the cardiovascular basic helix-loop-helix factor (CHF)1Hey2 gene show isolated ventricular septal defects. These defects result primarily in failure to thrive. Mice often succumbed within the first 3 wk after birth and showed pulmonary and liver congestion. The penetrance of this phenotype varied, depending on genetic background, suggesting the presence of modifier genes. Expression patterns of other cardiac-specific genes were not affected. Of the few animals on a mixed genetic background that survived to adulthood, most developed a cardiomyopathy but did not have ventricular septal defects. Our results indicate that CHF1 plays an important role in regulation of ventricular septation in mammalian heart development and is important for normal myocardial contractility. These mice provide a useful model for the study of the ontogeny and natural history of ventricular septal defects and cardiomyopathy. Show less