xxx

Gene: 1519	Name: Adcy7	Family: Cyclase	Subfamily: Adenylate	Accession: NM_007406	GI: 6680645

Gene 1519
Summary of Phenotypic Analysis

Changes related to genotype:

Lethality: Homozygous mice frequently do not survive to weaning age.

There were no significant differences detected in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

The genotypic ratio suggested either a perinatal or juvenile lethal phenotype.

ES cells derived from the 129/OlaHsd mouse substrain were used to generate chimeric mice. F1 mice were generated by breeding with C57BL/6 females. F2 homozygous and heterozygous mutant mice were produced by intercrossing F1 heterozygous males and females.

Wild-type control mice, and heterozygous and homozygous mutant mice, were evaluated by the following examinations or tests:

Physical examination
Necropsy, including body length, body weight, and organ weight measurements
Histological examination of tissues and organs
Bone marrow section evaluation
Complete blood counts and differential cell counts
Clinical chemistry panels
Densitometry
Aging studies

Gene 1519
Expression Summary

Taqman Summary:
The highest levels of RNA transcripts are detectable in lymph nodes and adrenal gland.

Moderate levels of RNA transcripts are detectable in lung, spleen, thymus, skin, gallbladder, urinary bladder, pituitary gland, testis, epididymis, prostate gland, ovary, uterus and white fat.

Lower levels of RNA transcripts are detectable in whole brain, cortex, subcortical region, cerebellum, brainstem, olfactory bulb, spinal cord, eye, Harderian glands, heart, liver, pancreas, kidney, bone marrow, salivary gland, skeletal muscle, tongue, stomach, small intestine, cecum, colon, seminal vesicle and coagulating gland.

LacZ Summary:
Striking lacZ expression was observed in several tissues. Strong expression was detected in the cardiovascular system in valves, atria and blood vessels of the heart and in aorta. The lung also showed strong X-Gal staining in blood vessels and alveoli with more moderate expression in bronchioles. Strong staining was observed in connective tissue of the skeletal muscle. Further, strong to moderate expression was detected in lymphoid tissues, including spleen, lymph nodes and thymus. Less prominent staining was observed in several other tissues.

LacZ expression was detected in: brain, thymus, spleen, lymph nodes, bone marrow, aorta, heart, lung, pancreas, kidney, urinary bladder, thyroid gland, skeletal muscle, skin, testis, prostate gland, ovary and uterus.

LacZ expression was not detected in: spinal cord, sciatic nerve, eyes, liver, pituitary gland and adrenal glands.

Gene 1519
Densitometry

There were no significant differences detected in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

The following mice were evaluated by dual-energy x-ray absorptiometry. The data were compiled from the F2N0 and F2N1 generations.

Densitometric Findings:

Incidental densitometric differences were present between some mice. These findings were considered to represent background differences occasionally seen in this strain of mice, differences due to spontaneous disease, age-related differences, and/or differences of a nonspecific etiology. They were not considered to be genotype related.

Gene 1519
Histopathology

There were no significant differences detected in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

Tissues from the following mice were evaluated histologically. The data were compiled from the F2N0 and F2N1 generations.

The following tissues were examined and considered to have no genotype-related abnormality: brain, pituitary gland, ears, nasal cavity, salivary glands, oral cavity, lymph nodes, aorta, lungs, liver, gallbladder, pancreas, spleen, kidneys, urinary bladder, stomach, small and large intestines, larynx, esophagus, trachea, thyroid gland, thymus gland, tongue, skeletal muscle, sciatic nerve, mammary glands, vertebrae, spinal cord, bone (skull, sternum, femur, tibia, and stifle joint), reproductive tract (including gonads), eyes, Harderian glands, integumentary system (skin and either clitoral or preputial glands), and bone marrow.

Bone marrow was examined in sections of sternum, vertebrae, and/or femur and tibia. Marrow cellularity, myeloid:erythroid (M:E) ratio, myeloid and erythroid maturation sequences, and numbers of megakaryocytes were evaluated.

Incidental lesions were present in some tissues. For example, in a 49 day cohort heterozygous female (270186) a pancreatic lesion noted at tissue trimming correlated with a pancreatic cyst. These findings were considered to represent background lesions occasionally seen in this strain of mice, lesions due to spontaneous disease, age-related lesions, and/or lesions of a nonspecific etiology. They were not considered to be genotype related.

Gene 1519
Necropsy

There were no significant differences detected in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

The following mice were necropsied. Body weight, body length, and organ weights were obtained, and gross pathological findings were recorded. The data are compiled from the F2N0 and F2N1 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (278972, 278975, 285608)
3 homozygous mutant males (268994, 274539, 280833)
3 heterozygous mutant females (268988, 268989, 270186)
3 heterozygous mutant males (267646, 270189, 280830)
2 wild-type control females (267649, 268984)
2 wild-type control males (269000, 270379)

300 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant females (269010, 269013)
2 heterozygous mutant males (282120, 282121)
1 wild-type control male (283060)

Mice were examined for the following observables: adrenal glands, body length, body weight, bone marrow, bone - cranium, bone - femur, bone - sternum, bone - stifle joint, bone - vertebral column, brain, cecum, colon, duodenum, epididymis - seminal vesicle, esophagus, eyes, gallbladder, general appearance, Harderian glands, heart, heart weight, ileum, jejunum, kidney weight, kidneys, liver, liver weight, lungs, lymph nodes, mesentery, ovaries, pancreas, penis, salivary glands, sciatic nerve, scrotum, skeletal muscle, skin, skinned mouse, spleen, spleen weight, stomach, testes, testes - epididymis weight, thymus, thymus weight, tongue, trachea, urinary bladder, urine, uterus, and vagina. (Gender-specific observables apply to the appropriate gender.)

Necropsy Findings:

There were no genotype-related or biologically significant differences noted between mutant and wild-type control mice for any of the parameters evaluated at necropsy. Incidental lesions were present in some tissues. For example, in the 49 day cohort a heterozygous mutant female (270186) was reported to have an inguinal mass that correlated with perinodal and subcutaneous acute inflammation and fat necrosis, and a peri-uterine mass that correlated with acute inflammation and fat necrosis of periovarian soft tissues, on histopathological examination. Additionally, in the 49 day cohort a homozygous mutant female (278972) and a homozygous mutant male (274539) were each reported to have a pancreatic nodule for which there were no histopathological correlates. These findings were considered to represent background lesions occasionally seen in this strain of mice, lesions due to spontaneous disease, age-related lesions, and/or lesions of a nonspecific etiology. They were not considered to be related to genotype.

Body and Organ Weight Findings:

Differences in body length, body weight, organ weights, and/or organ weight to body weight ratios were present between individual mice. The variability between mice usually fell within our historical reference ranges and was not correlated with genotype.

Gene 1519
Clinical Chemistry

There were no significant differences in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

Serum samples from the following mice were evaluated by a clinical chemistry panel. The data are compiled from the N0F2 and N1F2 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (278972, 278975, 285608)
3 homozygous mutant males (268994, 274539, 280833)
3 heterozygous mutant females (268989, 270185, 270186)
3 heterozygous mutant males (270189, 284757, 294430)
2 wild-type control females (268984, 294435)
2 wild-type control males (269000, 270379)

90 Day Cohort Mouse ID numbers are as follows:
4 heterozygous mutant females (269010, 269013, 270383, 270385)
2 heterozygous mutant males (285590, 285591)
4 wild-type control females (269007, 269012, 270382, 270384)
1 wild-type control male (281199)

180 Day Cohort Mouse ID numbers are as follows:
3 heterozygous mutant females (269010, 269013, 270385)
4 heterozygous mutant males (282120, 282121, 285590, 285591)
4 wild-type control females (269007, 269012, 270382, 270384)
4 wild-type control males (281199, 283060, 288281, 343321)

300 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant females (269010, 269013)
2 heterozygous mutant males (282120, 282121)
2 wild-type control females (269007, 269012)
2 wild-type control males (281199, 283060)

Values for the various analytes evaluated were generally similar between homozygous or heterozygous mutant, and wild-type control mice. Although variations in clinical chemistry values were present in some mice, they were not related to genotype and, thus, were not considered phenotypically relevant.

Gene 1519
Hematology

There were no significant differences in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

Blood samples from the following mice were evaluated by a complete blood count and differential cell count. The data are compiled from the N0F2 and N1F2 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (278972, 278975, 285608)
3 homozygous mutant males (274539, 280833, 306573)
3 heterozygous mutant females (268988, 268989, 270185)
3 heterozygous mutant males (270189, 274537, 280830)
2 wild-type control females (267649, 268984)
2 wild-type control males (269000, 270379)

90 Day Cohort Mouse ID numbers are as follows:
4 heterozygous mutant females (269010, 269013, 270383, 270385)
4 heterozygous mutant males (282120, 282121, 285590, 285591)
4 wild-type control females (269007, 269012, 270382, 270384)
5 wild-type control males (281199, 283060, 285485, 288281, 343321)

180 Day Cohort Mouse ID numbers are as follows:
4 heterozygous mutant males (282120, 282121, 285590, 285591)
4 wild-type control males (281199, 283060, 288281, 343321)

300 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant females (269010, 269013)
2 heterozygous mutant males (282120, 282121)
2 wild-type control females (269007, 269012)
2 wild-type control males (281199, 283060)

Although minor variations of hematological values were present in some mice, these changes were not related to genotype and, thus, were not considered phenotypically relevant.

Gene 1519
Physical Examination

There were no significant differences detected in the homozygous or heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

The following mice were evaluated by physical examination. The data were compiled from the F2N0 and F2N1 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (278972, 278975, 285608)
3 homozygous mutant males (268994, 274539, 280833)
3 heterozygous mutant females (268988, 268989, 270186)
3 heterozygous mutant males (267646, 270189, 280830)
2 wild-type control females (267649, 268984)
2 wild-type control males (269000, 270379)

300 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant females (269010, 269013)
2 heterozygous mutant males (282120, 282121)
2 wild-type control females (269007, 269012)
2 wild-type control males (281199, 283060)

Mice were examined in detail as follows: anus, behavior, body shape, claws, coat - fur, coat color - back, coat color - belly, ear - left, ear - right, eye - left, eye - right, eye color - left, eye color - right, feces, forelimb - left, forelimb - right, forelimb number of amputated digits - left, forelimb number of amputated digits - right, forelimb number of digits - left, forelimb number of digits - right, general appearance, genitals - female, genitals - male, hair type, head shape, hindlimb - left, hindlimb - right, hindlimb number of amputated digits - left, hindlimb number of amputated digits - right, hindlimb number of digits - left, hindlimb number of digits - right, injuries, lesions, limb shape, locomotor, lumps - masses, mammary glands, mice in cage, respiration, skin appearance, snout, swelling - joints, tail, teeth color, teeth length, urine, and whiskers. (Gender-specific observables apply to the appropriate gender.)

Individual homozygous or heterozygous mutant mice had only occasional minor differences in observed physical features compared to wild-type control mice. These findings were considered to represent individual variability, background features occasionally seen in this strain of mice, findings due to spontaneous disease, age-related findings, and/or findings of a nonspecific etiology. However, none of these differences was regarded as biologically significant or genotype related.

Gene 1519
Aging Metrics

There were no significant differences detected in the heterozygous mutant mice when compared with age- and gender-matched wild-type control mice.

Body weights and body lengths were measured for mice at 49, 90, 180, and 300 days of age.

49 Day Cohort Mouse ID numbers are as follows:
4 heterozygous mutant females (269010, 269013, 270383, 270385)
4 heterozygous mutant males (282120, 282121, 285590, 285591)
4 wild-type control females (269007, 269012, 270382, 270384)
6 wild-type control males (270379, 281199, 283060, 285485, 288281, 343321)

90 Day Cohort Mouse ID numbers are as follows:
4 heterozygous mutant females (269010, 269013, 270383, 270385)
4 heterozygous mutant males (282120, 282121, 285590, 285591)
4 wild-type control females (269007, 269012, 270382, 270384)
4 wild-type control males (281199, 283060, 288281, 343321)

180 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant males (282120, 282121)
3 wild-type control males (281199, 283060, 343321)

300 Day Cohort Mouse ID numbers are as follows:
2 heterozygous mutant females (270383, 270385)
4 heterozygous mutant males (285590, 285591, 288387, 288388)
3 wild-type control females (269007, 269012, 270382)
2 wild-type control males (281199, 288281)

Body Weight and Length Findings:

Differences in body length and body weight were present between individual mice. The variability between mice usually fell within our historical reference ranges and was not correlated with genotype.