Phenotypes associated with this allele

• Allele Symbol: Dhh^tm1Amc
• Allele Name: targeted mutation 1, Andrew P McMahon
• Allele ID: MGI:1934259
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Dhh^tm1Amc/Dhh^tm1Amc	involves: 129	MGI:2659084
hm2	Dhh^tm1Amc/Dhh^tm1Amc	involves: 129S1/Sv	MGI:2659066
hm3	Dhh^tm1Amc/Dhh^tm1Amc	involves: 129S1/Sv * C57BL/6J	MGI:2659067
hm4	Dhh^tm1Amc/Dhh^tm1Amc	involves: 129S1/Sv * C57BL/6J * Swiss Webster	MGI:2659090

Genotype
MGI:2659084

hm1

• Allelic Composition: Dhh^tm1Amc/Dhh^tm1Amc
• Genetic Background: involves: 129

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

nervous system

abnormal nervous system morphology ( J:57341 )

• sciatic nerve flattened rather than round in cross-section

• little collagen in epineurium

• few fibroblasts in epineurium but perineurium-like cells present

• 2-4 layers in perineurium as opposed to 6-8 layers normally

• discontinuous basal lamina in perineurium

• cell junction defects between perineurium cells

• perineurial-like cells invade endoneurial space

• defective nerve tissue barrier, granulocyte invasion of nerves in inflammation

Genotype
MGI:2659066

hm2

• Allelic Composition: Dhh^tm1Amc/Dhh^tm1Amc
• Genetic Background: involves: 129S1/Sv

endocrine/exocrine glands

abnormal seminiferous tubule morphology ( J:57914 )

♂ • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells

♂ • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost

abnormal Sertoli cell morphology ( J:57914 )

♂ • only a residual lining of Sertoli cells was observed in most males

small testis ( J:57914 )

♂ • at 18.5 dpc, homozygous mutant testes were grossly smaller than those of heterozygous littermates

♂ • a progressive reduction in testicular mass was observed amounting to a 60% decrease at P10 and a 90% decrease at 6 weeks of age

reproductive system

azoospermia ( J:57914 )

♂ • no mature sperm were detected in the testis or epididymis

abnormal spermatid morphology ( J:57914 )

♂ • spermatids were not observed

abnormal seminiferous tubule morphology ( J:57914 )

♂ • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells

♂ • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost

abnormal Sertoli cell morphology ( J:57914 )

♂ • only a residual lining of Sertoli cells was observed in most males

small testis ( J:57914 )

♂ • at 18.5 dpc, homozygous mutant testes were grossly smaller than those of heterozygous littermates

♂ • a progressive reduction in testicular mass was observed amounting to a 60% decrease at P10 and a 90% decrease at 6 weeks of age

arrest of spermatogenesis ( J:57914 )

♂ • Background Sensitivity: on an inbred 129/Sv background, primary spermatocytes were formed but underwent cell death and no spermatids were observed; in contrast, on a 129/Sv x C57BL/6J hybrid background, germ cells of some mice progressed through meiosis to late stages of spermiogenesis but sperm development was blocked at step 15

male infertility ( J:57914 )

♂ • male homozygotes were viable and displayed normal male anatomy and behavior but were infertile

♂ • in contrast, female homozygotes were fully fertile

cellular

azoospermia ( J:57914 )

♂ • no mature sperm were detected in the testis or epididymis

abnormal spermatid morphology ( J:57914 )

♂ • spermatids were not observed

Genotype
MGI:2659067

hm3

• Allelic Composition: Dhh^tm1Amc/Dhh^tm1Amc
• Genetic Background: involves: 129S1/Sv * C57BL/6J

endocrine/exocrine glands

abnormal seminiferous tubule morphology ( J:57914 )

♂ • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells

♂ • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost

abnormal Sertoli cell morphology ( J:57914 )

♂ • only a residual lining of Sertoli cells was observed in most males

small testis ( J:57914 )

♂ • a progressive reduction in testicular mass was grossly evident at 18.5 dpc

reproductive system

abnormal seminiferous tubule morphology ( J:57914 )

♂ • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells

♂ • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost

abnormal Sertoli cell morphology ( J:57914 )

♂ • only a residual lining of Sertoli cells was observed in most males

small testis ( J:57914 )

♂ • a progressive reduction in testicular mass was grossly evident at 18.5 dpc

abnormal spermatogenesis ( J:57914 )

♂ • Background Sensitivity: on a 129/Sv x C57BL/6J hybrid background, germ cells of some mice progressed through meiosis to late stages of spermiogenesis but sperm development was blocked at step 15; in contrast, on an inbred 129/Sv background, primary spermatocytes were formed but underwent cell death

azoospermia ( J:57914 )

♂ • no mature sperm were detected in the testis or epididymis

arrest of spermiogenesis ( J:57914 )

♂ • although step 15 spermatids were detected in tubules undergoing the transition from stage VI to stage VII, no step 16 spermatids were found in stage VII tubules, suggesting a developmental block at this stage

male infertility ( J:57914 )

♂ • male homozygotes were viable and displayed normal male anatomy and behavior but were infertile

♂ • in contrast, female homozygotes were fully fertile

cellular

azoospermia ( J:57914 )

♂ • no mature sperm were detected in the testis or epididymis

Genotype
MGI:2659090

hm4

• Allelic Composition: Dhh^tm1Amc/Dhh^tm1Amc
• Genetic Background: involves: 129S1/Sv * C57BL/6J * Swiss Webster

endocrine/exocrine glands

abnormal testis morphology ( J:65900 )

♂ • feminized males show numerous layers of fibroblast-like cells with abundant intervening collagen external to the seminiferous tubules

♂ • the fibrosis produced by the accumulation of collagen fibers in the interstitium of feminized testes increased with age

abnormal seminiferous tubule morphology ( J:65900 )

♂ • irregular and anastomotic tubules were observed in feminized adult males; tubular profiles were not rounded and the intertubular tissue displayed a few Leydig cells but extensive fibroblastic tissue

♂ • relatively normal tubule appearance in masculinized adult males with small Sertoli cells and abundant adult-type Leydig cells in the interstitial lymphatic space

abnormal peritubular myoid cell morphology ( J:65900 )

♂ • feminized males displayed immature myoid cells that were abnormally thickened instead of being flattened and lacked organized actin filaments and the pinocytotic vesicles observed in control testes

♂ • in some cases, the myoid cell layer around the seminiferous tubules was discontinuous, with only collagen in the place of absent cells

♂ • in some regions of feminized testes, the basement membrane between the myoid cell and cells of the seminiferous tubules was absent, whereas in other regions, the myoid cells gave rise to numerous microvilli that impinged upon the Sertoli cells

decreased number of peritubular myoid cells ( J:65900 )

♂ • at 20 days of age, no myoid cells or parietal lymphatic cells could be identified in feminized males

♂ • in some cases where the basement membrane was absent, there was a direct intermingling of Leydig cells with Sertoli cells without any intervening peritubular tissue or extracellular basal laminae

abnormal Sertoli cell morphology ( J:65900 )

♂ • in masculinized males, Sertoli cells were small and lacked a normal architecture in the relative absence of germ cells

♂ • in feminized males, absence of a basement membrane resulted in apolar Sertoli cells

abnormal testis cord formation ( J:65900 )

♂ • the basal lamina of seminiferous cords was not always continuous in newborn and adult mutant mice

abnormal Leydig cell morphology ( J:65900 )

♂ • masculinized adult males exhibited adult-type Leydig cells characterized by a dense cytoplasmic matrix, abundant smooth endoplasmic reticulum (SER), whorled ER, and a relative scarcity of lipid and glycogen, as well as an incomplete layer of parietal lymphatic endothelial cells external to the myoid cell layer

♂ • in contrast, feminized males lacked both adult-type Leydig cells and a complete layer of parietal lymphatic endothelial cells; a few clusters of fetal-type Leydig cells were observed, with relatively less SER, a less dense cytoplasmic matrix compared to adult-type Leydig cells, no whorled SER, and abundant lipid and glycoge

decreased Leydig cell number ( J:65900 )

♂ • significant reduction or near absence of adult-type Leydig cells in the interstitial testicular region of feminized males

♂ • the relatively few Leydig cells that were present were identified as fetal based on their distinct morphology

increased Leydig cell number ( J:65900 )

♂ • abundance of adult-type Leydig cells in the interstitial lymphatic space of masculinized males

small testis ( J:65900 )

♂ • extremely reduced size of testes in both masculinized and feminized males

♂ • testes of masculinized males were larger than those of feminized males

decreased testis weight ( J:65900 )

♂ • the mean paired testis weight of feminized males was reduced to only 5% of that in heterozygous control mice

cryptorchism ( J:65900 )

♂ • mutant testes were embedded in the fat pads in proximity to the kidneys

homeostasis/metabolism

decreased circulating testosterone level ( J:65900 )

♂ • reduced levels of circulating testosterone in feminized males relative to controls (1.39 0.05 ng/ml vs 3.6 0.64 ng/ml, respectively)

increased circulating luteinizing hormone level ( J:65900 )

♂ • increased levels of circulating LH in feminized males relative to controls (14.1 2.5 ng/ml vs 4.9 1.0 ng/ml, respectively)

♂ • normal serum levels of follicle stimulating hormone (FSH) in feminizied males relative to controls

reproductive system

abnormal male germ cell morphology ( J:65900 )

♂ • in newborn (1-day-old) mice, germ cells were largely present within the seminiferous cords, but many were also found outside the cords

♂ • no synaptonemal complexes were noted in extracordal germ cells, indicating that meiotic development had not occurred

♂ • by 8 days of age, nearly all extracordal germ cells had been lost

abnormal spermatogonia morphology ( J:65900 )

♂ • rare spermatogonia were observed in feminized adult males

abnormal anogenital distance ( J:65900 )

♂ • masculinized males displayed a relatively longer urogenital-anal distance than feminized males

abnormal testis morphology ( J:65900 )

♂ • feminized males show numerous layers of fibroblast-like cells with abundant intervening collagen external to the seminiferous tubules

♂ • the fibrosis produced by the accumulation of collagen fibers in the interstitium of feminized testes increased with age

abnormal seminiferous tubule morphology ( J:65900 )

♂ • irregular and anastomotic tubules were observed in feminized adult males; tubular profiles were not rounded and the intertubular tissue displayed a few Leydig cells but extensive fibroblastic tissue

♂ • relatively normal tubule appearance in masculinized adult males with small Sertoli cells and abundant adult-type Leydig cells in the interstitial lymphatic space

abnormal peritubular myoid cell morphology ( J:65900 )

♂ • feminized males displayed immature myoid cells that were abnormally thickened instead of being flattened and lacked organized actin filaments and the pinocytotic vesicles observed in control testes

♂ • in some cases, the myoid cell layer around the seminiferous tubules was discontinuous, with only collagen in the place of absent cells

♂ • in some regions of feminized testes, the basement membrane between the myoid cell and cells of the seminiferous tubules was absent, whereas in other regions, the myoid cells gave rise to numerous microvilli that impinged upon the Sertoli cells

decreased number of peritubular myoid cells ( J:65900 )

♂ • at 20 days of age, no myoid cells or parietal lymphatic cells could be identified in feminized males

♂ • in some cases where the basement membrane was absent, there was a direct intermingling of Leydig cells with Sertoli cells without any intervening peritubular tissue or extracellular basal laminae

abnormal Sertoli cell morphology ( J:65900 )

♂ • in masculinized males, Sertoli cells were small and lacked a normal architecture in the relative absence of germ cells

♂ • in feminized males, absence of a basement membrane resulted in apolar Sertoli cells

abnormal testis cord formation ( J:65900 )

♂ • the basal lamina of seminiferous cords was not always continuous in newborn and adult mutant mice

abnormal Leydig cell morphology ( J:65900 )

♂ • masculinized adult males exhibited adult-type Leydig cells characterized by a dense cytoplasmic matrix, abundant smooth endoplasmic reticulum (SER), whorled ER, and a relative scarcity of lipid and glycogen, as well as an incomplete layer of parietal lymphatic endothelial cells external to the myoid cell layer

♂ • in contrast, feminized males lacked both adult-type Leydig cells and a complete layer of parietal lymphatic endothelial cells; a few clusters of fetal-type Leydig cells were observed, with relatively less SER, a less dense cytoplasmic matrix compared to adult-type Leydig cells, no whorled SER, and abundant lipid and glycoge

decreased Leydig cell number ( J:65900 )

♂ • significant reduction or near absence of adult-type Leydig cells in the interstitial testicular region of feminized males

♂ • the relatively few Leydig cells that were present were identified as fetal based on their distinct morphology

increased Leydig cell number ( J:65900 )

♂ • abundance of adult-type Leydig cells in the interstitial lymphatic space of masculinized males

small testis ( J:65900 )

♂ • extremely reduced size of testes in both masculinized and feminized males

♂ • testes of masculinized males were larger than those of feminized males

decreased testis weight ( J:65900 )

♂ • the mean paired testis weight of feminized males was reduced to only 5% of that in heterozygous control mice

cryptorchism ( J:65900 )

♂ • mutant testes were embedded in the fat pads in proximity to the kidneys

abnormal spermatogenesis ( J:65900 )

♂ • both masculinized (7.5%) and feminized (92.5%) males showed abnormal peritubular tissue and severely depressed spermatogenesis

abnormal spermatocyte morphology ( J:65900 )

♂ • spermatogonia were evident but only a few spermatocytes were observed in masculinized adult males

♂ • rare spermatocytes were observed in feminized adult males

male pseudohermaphroditism ( J:65900 )

♂ • 92.5% of mutant males were pseudohermaphrodites with an external female phenotype, evidence of mammary teats, and a blind vaginal opening; the remaining 7.5% mutant males were masculinized

♂ • penetrance within the 92.5% varied; for example, some males were only partly feminized with colored teat hairs but lacking a blind vaginal opening

♂ • internally, masculinized males were similar to feminized males except that the overall size of the reproductive tract was relatively larger, although still smaller, than that of wild-type or heterozygous controls

male infertility ( J:65900 )

♂

digestive/alimentary system

abnormal anogenital distance ( J:65900 )

♂ • masculinized males displayed a relatively longer urogenital-anal distance than feminized males

cellular

abnormal male germ cell morphology ( J:65900 )

♂ • in newborn (1-day-old) mice, germ cells were largely present within the seminiferous cords, but many were also found outside the cords

♂ • no synaptonemal complexes were noted in extracordal germ cells, indicating that meiotic development had not occurred

♂ • by 8 days of age, nearly all extracordal germ cells had been lost

abnormal spermatocyte morphology ( J:65900 )

♂ • spermatogonia were evident but only a few spermatocytes were observed in masculinized adult males

♂ • rare spermatocytes were observed in feminized adult males

abnormal spermatogonia morphology ( J:65900 )

♂ • rare spermatogonia were observed in feminized adult males

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
46,XY sex reversal		DOID:14448	OMIM:607080 OMIM:PS400044	J:65900