We cloned a new imprinted gene by searching for parental-origin-specific CpG methylations using methylation-sensitive two-dimensional genome scanning method. This gene encodes a putative 51 kDa protein with significant similarity to U2 small nuclear ribonucleoprotein auxiliary factor small subunits, an essential mammalian splicing factor, and is located on mouse chromosome 11, of which maternal duplication/paternal deficiency results in a small body.

AMP deaminase (AMPD) plays a central role in preserving the adenylate energy charge in myocytes following exercise and in producing intermediates for the citric acid cycle in muscle. Prior studies have demonstrated that AMPD1 binds to myosin heavy chain (MHC) in vitro; binding to the myofibril varies with the state of muscle contraction in vivo, and binding of AMPD1 to MHC is required for activation of this enzyme in myocytes. The present study has identified three domains in AMPD1 that influence binding of this enzyme to MHC using a cotransfection model that permits assessment of mutations introduced into the AMPD1 peptide. One domain that encompasses residues 178–333 of this 727-amino acid peptide is essential for binding of AMPD1 to MHC. This region of AMPD1 shares sequence similarity with several regions of titin, another MHC binding protein. Two additional domains regulate binding of this peptide to MHC in response to intracellular and extracellular signals. A nucleotide binding site, which is located at residues 660–674, controls binding of AMPD1 to MHC in response to changes in intracellular ATP concentration. Deletion analyses demonstrate that the amino-terminal 65 residues of AMPD1 play a critical role in modulating the sensitivity to ATP-induced inhibition of MHC binding. Alternative splicing of the AMPD1 gene product, which alters the sequence of residues 8–12, produces two AMPD1 isoforms that exhibit different MHC binding properties in the presence of ATP. These findings are discussed in the context of the various roles proposed for AMPD in energy production in the myocyte.

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2–3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols.

A 66-year-old Japanese man presented with persistent hyponatremia without polydipsia and polyuria. Laboratory examination showed serum sodium of 117 mEq/l, plasma osmolality 239mosm/kg, urine sodium 108mEq/l, urine osmolality 577 mosm/kg, and normal levels (<2.0 pg/ml) of serum antidiuretic hormone (ADH). ADH release was regulated normally with changes in plasma osmolality. No obvious cause for the syndrome of inappropriate secretion of ADH (SIADH) could be detected. However, 20 months later, the patient had bouts of hematuria and was found to have cancer of the urinary bladder. Increased renal sensitivity to ADH was suspected as the underlying mechanism of SIADH. (Internal Medicine 31: 246-250, 1992)

A 13-kb fragment of the rat aldolase C gene contains sufficient information for gene expression. Transgenic mice carrying the 13-kb fragment showed restoration of chromatin structure and tissue-specific, copy number-dependent expression. To localize the regulatory elements responsible for restoring chromatin structure, several mutated constructs were used to produce transgenic mice. Three activities were examined: recreation of DNase hypersensitive sites, restoration of methylation status, and copy number-dependent expression. Deletions of the 3'-flanking region did not affect those activities. Deletion of seven introns affected the mRNA levels but not the restoration of the chromatin structure. The insertion of the LacZ gene into the first exon of the transgene interfered with both the restoration of the chromatin structure and the copy number-dependent expression in transgenic mice. DNase I footprinting assays revealed that brain-specific factors bind to the sequence disrupted by the LacZ insertion. These results suggest that the sequence in the first exon is essential for restoring the chromatin structure of the rat aldolase C gene.