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Gene: 693	Name: Birc1a	Family: Apoptosis Pathway	Subfamily: Apoptosis Inhibitor	Accession: AF007769	GI: 2352684

Gene 693
Summary of Phenotypic Analysis

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

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. The resultant F1N0 heterozygotes were backcrossed to C57BL/6 mice to generate F1N1 heterozygotes. F2N1 heterozygous mutant mice were produced by intercrossing F1N1 heterozygous males and females. F2N2 homozygous and heterozygous mutant, and wild-type mice were produced by a second backcross.

Wild-type control mice 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
Fertility tests
Aging studies

Gene 693
Fertility

Both homozygous mutant males and females were fertile. Their progeny were viable until weaning.

Three homozygous mutant mice of each gender were set up in a fertility mating one on one with each other at seven to ten weeks of age. The number of pups born from three litters was recorded. Three weeks later, the live pups were counted and weaned.

Mouse ID numbers are as follows:

3 homozygous mutant males (248087, 281733, 284993)

3 homozygous mutant females (263230, 281737, 281740)

Gene 693
Expression Summary

RT-PCR Summary:
High levels of RNA transcripts are detectable in small intestine, large intestine and cecum.

Lower levels of RNA transcripts are also detectable in: brainstem, spinal cord, Harderian glands, heart, lung, liver, pancreas, kidney, spleen, thymus, lymph nodes, bone marrow, skin, gallbladder, urinary bladder, pituitary gland, adrenal gland, salivary gland, skeletal muscle, tongue, stomach, testis, epididymis, seminal vesicle, coagulating gland, prostate gland, ovaries, uterus and white fat.

No RNA transcripts are detectable in brain, cortex, subcortical region, cerebellum, olfactory bulb and eye.

LacZ Summary:
LacZ expression was not detected in any tissues or organs analyzed: brain, spinal cord, sciatic nerve, eyes, Harderian glands, thymus, spleen, lymph nodes, bone marrow, aorta, heart, lung, liver, gallbladder, pancreas, kidney, urinary bladder, larynx, esophagus, thyroid gland, parathyroid gland, pituitary gland, adrenal glands, salivary glands, tongue, skeletal muscle, skin, male and female reproductive systems.

Gene 693
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.

Densitometric Findings:

Densitometric differences between mice, including fat% decreased, were present that occasionally occur spontaneously. In this target, such differences were present in two homozygous male mice at 300 days(248084, 248085) . We have not reported these findings as phenotypic changes, but we have presented them here for your consideration.
Other incidental densitometric differences may have been 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 693
Histopathology

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

Tissues from the following mice were evaluated histologically.

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, 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, a 49 day cohort homozygous mutant male (237250) was reported to have an adenocarcinoma of the tongue. 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 693
Necropsy

There were no significant differences detected in the homozygous 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.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (237251, 237253, 237255)
3 homozygous mutant males (237248, 237250, 250937)
1 wild-type control female (237263)
2 wild-type control males (237267, 237270)

300 Day Cohort Mouse ID numbers are as follows:
2 homozygous mutant females (248089, 250939)
3 homozygous mutant males (237265, 248084, 248085)
1 wild-type control male (253850)

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 may have been present in some tissues. 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.

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 693
Clinical Chemistry

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

Serum samples from the following mice were evaluated by a clinical biochemistry panel. The data are compiled from the N1F2 and N2F2 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (237251, 237253, 237255)
3 homozygous mutant males (237248, 237250, 250937)
2 wild-type control females (237263, 237264)
2 wild-type control males (237267, 237270)

90 Day Cohort Mouse ID numbers are as follows:
5 homozygous mutant females (248089, 250939, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
3 wild-type control females (250940, 274771, 274772)
4 wild-type control males (237266, 253850, 274770, 281735)

180 Day Cohort Mouse ID numbers are as follows:
1 homozygous mutant male (237265)
3 wild-type control females (274771, 274772, 292036)
3 wild-type control males (237266, 274768, 274770)

300 Day Cohort Mouse ID numbers are as follows:
2 homozygous mutant females (248089, 250939)
2 homozygous mutant males (237265, 248084)
2 wild-type control females (250940, 274771)
2 wild-type control males (237266, 253850)

Values for the various analytes evaluated were generally similar between homozygous 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 693
Hematology

There were no significant differences in the homozygous 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 N1F2 and N2F2 generations.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (237251, 237253, 237255)
3 homozygous mutant males (237248, 237250, 250937)
1 wild-type control female (237263)
2 wild-type control males (237267, 237270)

90 Day Cohort Mouse ID numbers are as follows:
4 homozygous mutant females (248089, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
4 wild-type control females (250940, 274771, 274772, 292036)
4 wild-type control males (237266, 253850, 274768, 274770)

180 Day Cohort Mouse ID numbers are as follows:
5 homozygous mutant females (248089, 250939, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
3 wild-type control females (274771, 274772, 292036)
4 wild-type control males (237266, 253850, 274768, 274770)

300 Day Cohort Mouse ID numbers are as follows:
2 homozygous mutant females (248089, 250939)
3 homozygous mutant males (237265, 248084, 248085)
2 wild-type control females (250940, 274771)
2 wild-type control males (237266, 253850)

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 693
Physical Examination

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

The following mice were evaluated by physical examination.

49 Day Cohort Mouse ID numbers are as follows:
3 homozygous mutant females (237251, 237253, 237255)
3 homozygous mutant males (237248, 237250, 250937)
1 wild-type control female (237263)
2 wild-type control males (237267, 237270)

300 Day Cohort Mouse ID numbers are as follows:
2 homozygous mutant females (248089, 250939)
3 homozygous mutant males (237265, 248084, 248085)
2 wild-type control females (250940, 274771)
2 wild-type control males (237266, 253850)

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, feces color, feces exam, 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, urine color, urine exam, and whiskers. (Gender-specific observables apply to the appropriate gender.)

Individual homozygous 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 693
Aging Metrics

There were no significant differences detected in the homozygous 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:
5 homozygous mutant females (248089, 250939, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
4 wild-type control females (248092, 250940, 274771, 274772)
4 wild-type control males (237266, 253850, 274768, 274770)

90 Day Cohort Mouse ID numbers are as follows:
5 homozygous mutant females (248089, 250939, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
4 wild-type control females (250940, 274771, 274772, 292036)
4 wild-type control males (237266, 253850, 274768, 274770)

180 Day Cohort Mouse ID numbers are as follows:
5 homozygous mutant females (248089, 250939, 250941, 253853, 253857)
4 homozygous mutant males (237265, 248084, 250929, 250931)
2 wild-type control females (250940, 292036)
2 wild-type control males (237266, 253850)

300 Day Cohort Mouse ID numbers are as follows:
4 homozygous mutant females (250939, 250941, 253853, 253857)
3 homozygous mutant males (237265, 248085, 250931)
3 wild-type control females (250940, 274771, 274772)
4 wild-type control males (237266, 253850, 274768, 274770)

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.