All Phenotypes Sh3pxd2b<nee> MGI Mouse

growth/size/body

short snout ( J:153369 )

• in all homozygotes

decreased body size ( J:153369 , J:262132 )

• at P17, homozygotes are ~15% smaller than wild-type controls (J:262132)

• by 2 months of age homozygotes have a dramatically lower body weight than controls and do not continue to grow after 2 months of age

proportional dwarf ( J:153369 )

abnormal postnatal growth ( J:153369 )

• mice stop growing at 2 months of age

craniofacial

decreased cranium height ( J:153369 )

domed cranium ( J:153369 )

• in all homozygotes

short snout ( J:153369 )

• in all homozygotes

skeleton

decreased cranium height ( J:153369 )

domed cranium ( J:153369 )

• in all homozygotes

decreased bone mineral density ( J:153369 )

• DEXA analysis shows reduced bone mineral density in both males and females with females having even lower density than males

abnormal skeleton development ( J:153369 )

• proportionally smaller skeleton

reproductive system

infertility ( J:153369 )

• both female and male homozygotes are infertile

female infertility ( J:153369 )

• although homozygous females are infertile, the ovaries function normally when transplanted into a normal host

male infertility ( J:153369 )

vision/eye

hyphema ( J:262132 )

• mild hyphema is occasionally present in the anterior segment of the eye at 3 months of age

cornea vascularization ( J:262132 )

• corneal neovascularization is frequently observed by 10 months of age

eye inflammation ( J:262132 )

• only 2 of 19 eyes, containing hypermature cataracts, exhibit infiltration of leukocytes in the posterior eye segment

hypopyon ( J:262132 )

• occasional presence of large, inferiorly located pools of white cellular infiltrate (hypopyon) in the anterior segment of the eye at 3 months of age

optic nerve cupping ( J:262132 )

• severe optic nerve head excavation extending beyond the choroid at 3 months of age

optic nerve degeneration ( J:262132 )

• optic nerves show severe axon degeneration and areas of gliosis by 3 months of age

• although myelinated axons appear to be sparser at P17, no signs of damaged axons are detected at this age

optic nerve atrophy ( J:262132 )

• all eyes exhibit advanced optic nerve head atrophy by 3 months of age

• at 3 months of age, the cross-sectional area of the optic nerve is significantly reduced, consistent with a severe glaucomatous progression

abnormal iridocorneal angle ( J:262132 )

• abnormal development of the iridocorneal angle leading to severe ocular disease

absent Schlemm's canal ( J:262132 )

absent trabecular meshwork ( J:262132 )

irregularly shaped pupil ( J:262132 )

• occasionally misshapen pupils at P17

anterior iris synechia ( J:153369 , J:262132 )

• severe peripheral anterior synechiae are found in all homozygotes (J:153369)

• at P17, all eyes exhibit severe iridocorneal adhesions around the entire circumference of the eye that persist to 10 months of age (J:262132)

decreased cornea thickness ( J:262132 )

• significantly decreased central corneal thickness at 1 month of age

cornea opacity ( J:153369 , J:262132 )

• eyes are typically bulging with white corneal opacities, which are present to varying degree in all homozygotes (J:153369)

• focal corneal opacities are first observed at 1 month of age (J:262132)

• by 3 months of age, corneal opacities are observed in all homozygotes (J:262132)

abnormal eye anterior chamber morphology ( J:262132 )

• eyes exhibit anterior segment dysgenesis and early-onset glaucoma

abnormal aqueous humor ( J:262132 )

• severe iridocorneal adhesions presumably result in aqueous humor outflow blockage

increased eye anterior chamber depth ( J:153369 , J:262132 )

• the anterior chamber of the eye has a larger depth than normal (J:153369)

• enlarged anterior chamber depth at 3 months of age (J:262132)

enlarged eye anterior chamber ( J:153369 , J:262132 )

• anterior chamber enlargement is first observed at 1 month of age (J:262132)

• by 3 months of age, enlarged anterior chambers are observed in all homozygotes (J:262132)

cataract ( J:262132 )

• cataract formation is frequently observed at 3 months of age

• by 9-15 months of age, all eyes show some form of lens abnormality ranging from the presence of posteriorly located swollen cells (5 of 8 eyes) to hypermature cataracts (3 of 8 eyes)

mature cataract ( J:262132 )

• at 3 months of age, 7 of 19 eyes exhibit hypermature cataracts characterized by complete cortical and nuclear opacification with a wrinkled lens capsule

posterior subcapsular cataract ( J:262132 )

• at 3 months of age, 4 of 19 eyes exhibit a posterior subcapsular cataract

exophthalmos ( J:153369 )

abnormal retina morphology ( J:262132 )

• all retinas show indices of glaucomatous damage at 3 months of age

retina ganglion cell degeneration ( J:262132 )

• striking retinal ganglion cell loss, optic nerve head excavation, and axon loss at 3-4 months of age

abnormal retina nerve fiber layer morphology ( J:262132 )

• thinning of the retinal nerve fiber layer at 3 months of age

decreased total retina thickness ( J:262132 )

• panretinal thinning involving multiple layers is observed to various degrees with increasing age

ocular hypertension ( J:262132 )

• intraocular pressure (IOP) is significantly elevated (30.8 +/- 12.5 mmHg) at 3-4 months of age; similar IOP values are obtained at the earliest and latest time points tested (1.4 and 14.6 months of age)

nervous system

gliosis ( J:262132 )

• optic nerves show severe axon degeneration and areas of gliosis at 3 months of age

retina ganglion cell degeneration ( J:262132 )

• striking retinal ganglion cell loss, optic nerve head excavation, and axon loss at 3-4 months of age

optic nerve cupping ( J:262132 )

• severe optic nerve head excavation extending beyond the choroid at 3 months of age

optic nerve degeneration ( J:262132 )

• optic nerves show severe axon degeneration and areas of gliosis by 3 months of age

• although myelinated axons appear to be sparser at P17, no signs of damaged axons are detected at this age

optic nerve atrophy ( J:262132 )

• all eyes exhibit advanced optic nerve head atrophy by 3 months of age

• at 3 months of age, the cross-sectional area of the optic nerve is significantly reduced, consistent with a severe glaucomatous progression

cardiovascular system

hyphema ( J:262132 )

• mild hyphema is occasionally present in the anterior segment of the eye at 3 months of age

cornea vascularization ( J:262132 )

• corneal neovascularization is frequently observed by 10 months of age

adipose tissue

decreased white adipose tissue amount ( J:153369 )

• adult homozygotes have severely depleted visceral and subcutaneous white adipose tissue but normal brown adipose tissue, and this is less striking in young homozygotes

hearing/vestibular/ear

abnormal middle ear morphology ( J:153369 )

• serous fluid with diffuse neutrophils is found in the middle-ear cavities of all homozygotes and the surrounding epithelium is thickened by fibrous connective tissue and embedded neutrophils

increased or absent threshold for auditory brainstem response ( J:153369 )

• elevated thresholds to broad-band click and 8, 16, and 32 kHz pure tone stimuli at all ages tested, from 34 to 92 days of age

increased susceptibility to otitis media ( J:153369 )

immune system

increased susceptibility to otitis media ( J:153369 )

eye inflammation ( J:262132 )

• only 2 of 19 eyes, containing hypermature cataracts, exhibit infiltration of leukocytes in the posterior eye segment

hypopyon ( J:262132 )

• occasional presence of large, inferiorly located pools of white cellular infiltrate (hypopyon) in the anterior segment of the eye at 3 months of age

cellular

gliosis ( J:262132 )

• optic nerves show severe axon degeneration and areas of gliosis at 3 months of age

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
glaucoma	DOID:1686		J:262132
otitis media	DOID:10754		J:153369

craniofacial

abnormal craniofacial morphology ( J:378753 )

• severe craniofacial dysmorphology

abnormal cranial suture morphology ( J:378753 )

• mice exhibit disrupted suture patterning with lack of mineralization and calcification in the membranous area proximal to the posterofrontal (PF) and sagittal sutures

abnormal metopic suture morphology ( J:378753 )

• normal architecture of the posterofrontal (PF) sutures is lost, endocranial and ectocranial layers are not distinguishable, and the PF suture remains patent; neither cartilage formation nor closure is observed at any time

• lack of endochondral ossification in PF sutures is confirmed by immunofluorescence staining for specific chondrogenic markers; no immunofluorescent signal is detected for SOX9 and COL2A1 at P8 or COL10A1 and BGLAP at P12, unlike in wild-type controls

• at P8, tartrate-resistant acid phosphatase (TRAP) staining shows that the typical osteolytic lacunae seen in the wild-type PF suture are absent and the entire suture region consists of suture mesenchyme lacking TRAP-positive cells

• by P12 and P30, osteoclasts have retracted to the lateral edges of the frontal bone and osteoclast activity (as measured by TRAP staining) is reduced within the suture area, suggesting impaired and spatially restricted osteoclastic remodeling in the PF suture

• at P3, PF sutures show reduced SH3PXD2B/TKS4 immunofluorescence staining in the suture mesenchyme, periosteum and dura mater relative to wild-type PF sutures

• however, no differences in SH3PXD2B/TKS4 levels are noted in the presumptive head area at E9.5

wide metopic suture ( J:378753 )

• enlarged, widely patent posterofrontal sutures at P30

abnormal sagittal suture morphology ( J:378753 )

• Movat s Pentachrome staining of sagittal sutures shows only suture mesenchyme with hypo-mineralization starting around P30 and ectopic bone formation at 6 months of age

• however, no changes in SH3PXD2B/TKS4 staining are noted in sagittal sutures at P3

wide sagittal suture ( J:378753 )

• enlarged, widely patent sagittal sutures at P30

decreased cranium height ( J:378753 )

• skulls are shortened along the anterior-posterior axis at P30

short nasal bone ( J:378753 )

• shortened nasal bones at P30

domed cranium ( J:378753 )

• domed skull

ectopic cranial bone ( J:378753 )

• sagittal sutures show ectopic bone formation at 6 months of age

short snout ( J:378753 )

• shortened nose

skeleton

decreased osteoblast proliferation ( J:378753 )

• percentage of EdU-positive osteoblasts is only 9% versus 40% in wild-type cells

• however, TUNEL assays show no differences in the apoptotic activity of osteoblasts in vitro and in vivo

abnormal osteoclast physiology ( J:378753 )

• mice exhibit reduced osteogenic potential accompanied by impaired osteoclast localization and activity during PF suture remodeling

abnormal bone healing ( J:378753 )

• following creation of a 2-mm calvarial defect in the parietal bone, mice exhibit an increase in the defect area over time, unlike wild-type controls which show minimal healing with limited bone regeneration from the periphery to the center in the defect area

• however, no TRAP activity is detected within the defect area itself at postoperative week 18, indicating that progressive defect enlargement is not due to excessive osteoclast activity at the injury site, but likely reflects deficient osteogenic repair capacity

abnormal skeleton morphology ( J:378753 )

• skeleton is smaller than in wild-type controls

abnormal cranial suture morphology ( J:378753 )

• mice exhibit disrupted suture patterning with lack of mineralization and calcification in the membranous area proximal to the posterofrontal (PF) and sagittal sutures

abnormal metopic suture morphology ( J:378753 )

• at P3, PF sutures show reduced SH3PXD2B/TKS4 immunofluorescence staining in the suture mesenchyme, periosteum and dura mater relative to wild-type PF sutures

• however, no differences in SH3PXD2B/TKS4 levels are noted in the presumptive head area at E9.5

wide metopic suture ( J:378753 )

• enlarged, widely patent posterofrontal sutures at P30

abnormal sagittal suture morphology ( J:378753 )

• Movat s Pentachrome staining of sagittal sutures shows only suture mesenchyme with hypo-mineralization starting around P30 and ectopic bone formation at 6 months of age

• however, no changes in SH3PXD2B/TKS4 staining are noted in sagittal sutures at P3

wide sagittal suture ( J:378753 )

• enlarged, widely patent sagittal sutures at P30

decreased cranium height ( J:378753 )

• skulls are shortened along the anterior-posterior axis at P30

short nasal bone ( J:378753 )

• shortened nasal bones at P30

domed cranium ( J:378753 )

• domed skull

ectopic cranial bone ( J:378753 )

• sagittal sutures show ectopic bone formation at 6 months of age

abnormal osteoblast morphology ( J:378753 )

• osteoblasts exhibit focally condensed perinuclear accumulation of SH3PXD2B/TKS4 rather than the uniform perinuclear expression seen in wild-type osteoblasts

• unstimulated and TGF-beta-stimulated osteoblasts show perinuclear cortactin accumulation with small, unevenly distributed cortactin-rich puncta in the cytoplasm that do not colocalize with F-actin or localize to the cell membrane; cell protrusions do not form

impaired osteoblast differentiation ( J:378753 )

• after 3 weeks in osteoinduction culture, osteoblasts show significantly decreased bone nodules formation and extracellular matrix mineralization, as determined by quantification of Alizarin Red staining

failure of endochondral bone ossification ( J:378753 )

• no endochondral ossification is detected in PF sutures by Movat s Pentachrome staining, unlike in wild-type controls where the endocranial layer undergoes closure via endochondral ossification between P8 and P12

cellular

abnormal intracellular organelle morphology ( J:378753 )

• following stimulation of cell migration with TGF-beta, the % of dura mater cells with podosome formation is significantly lower than in TGF-beta-stimulated wild-type dura mater cells

• % of osteoblasts with podosome formation is significantly decreased under both unstimulated and TGF-beta-stimulated conditions

• overall, dura mater cells and osteoblasts form fewer and structurally aberrant podosomes necessary for cell migration relative to wild-type cells

• migrating cranial NCCs show impaired podosome formation

impaired osteoblast differentiation ( J:378753 )

abnormal cranial neural crest cell migration ( J:378753 )

• in vitro, SOX10+ cranial NCCs from E9.5 neural plate tissue exhibit slower migration than wild-type NCCs over a 72-h period

• migrating NCCs show impaired podosome formation

• however, migrating NCCs show normal SH3PXD2B/TKS4 expression and distribution

decreased cell migration ( J:378753 )

• in vitro migration of dura mater cells is decreased at 24 h, as assessed by a scratch assay

• following creation of a 2-mm circular defect in the parietal bone, no migration of cells into the defect area is observed at 24 and 48 h postoperatively, unlike in wild-type controls

• however, in vitro migration of osteoblasts is comparable to that in wild-type cells

decreased cell proliferation ( J:378753 )

• percentage of EdU-positive dura mater cells is only 16% versus 37% in wild-type cells

• PCNA staining shows decreased proliferation in the surface ectoderm and adjacent mesenchymal layers of the presumptive head area at E9.5, as well as decreased proliferation in the PF and sagittal suture mesenchyme, periosteum and dura mater with normal proliferation detected in the bone plates

• however, TUNEL assays show no differences in the apoptotic activity of dura mater cells in vitro and in vivo

decreased cranial neural crest cell proliferation ( J:378753 )

• proliferation of cranial NCCs is generally reduced in the neural plate (NP) from E9.5 embryos; PCNA staining is more enhanced in the outer layer and focally present in sublayers of the NP, suggesting the presence of specific subpopulations of proliferative cells in the NP

• however, SH3PXD2B/TKS4 expression is normal and TUNEL assays show no differences in apoptotic activity in the NP relative to wild-type controls

decreased osteoblast proliferation ( J:378753 )

• percentage of EdU-positive osteoblasts is only 9% versus 40% in wild-type cells

• however, TUNEL assays show no differences in the apoptotic activity of osteoblasts in vitro and in vivo

abnormal ribosome biogenesis ( J:378753 )

• transcriptomic analysis on whole-mount skulls from P15 mice suggests downregulation of multiple genes involved in ribosome biogenesis, including SNORD genes and nuclear-encoded rRNA 5S

• Agilent Bioanalyzer analysis of RNA extracted from skull tissue shows a reduction in both small RNA concentration and relative microRNA proportion

• ribosomal RNA accumulates in the cell protrusions of migrating NCCs

embryo

abnormal cranial neural crest cell migration ( J:378753 )

• in vitro, SOX10+ cranial NCCs from E9.5 neural plate tissue exhibit slower migration than wild-type NCCs over a 72-h period

• migrating NCCs show impaired podosome formation

• however, migrating NCCs show normal SH3PXD2B/TKS4 expression and distribution

decreased cranial neural crest cell proliferation ( J:378753 )

• however, SH3PXD2B/TKS4 expression is normal and TUNEL assays show no differences in apoptotic activity in the NP relative to wild-type controls

abnormal cranial neural crest cell morphology ( J:378753 )

• migrating NCCs exhibit increased cortactin staining near cell membranes but cell boundaries appear frayed, the cytoskeleton is in disarray, and cell membranes appear to collapse; podosomes are not formed

nervous system

abnormal cranial neural crest cell morphology ( J:378753 )

abnormal brain dura mater morphology ( J:378753 )

• unstimulated dura mater cells show uneven cortactin accumulation in perinuclear regions, with pronounced focal staining while cell protrusions are absent and cell membranes appear frayed

• neural crest-derived dura mater cells show altered intracellular spatial distribution of SH3PXD2B/TKS4, with less intense nuclear immunofluorescence staining and increased perinuclear, focally condensed accumulation with less cytoplasmic expression relative to wild-type cells

• altered intracellular SH3PXD2B/TKS4 distribution is more pronounced in dura mater cells than in osteoblasts

• following TGF-beta stimulation, dura mater cells form protrusions, and cortactin and actin colocalize along the cell membrane while also showing enhanced perinuclear accumulation and no cytoplasmic distribution

homeostasis/metabolism

abnormal bone healing ( J:378753 )

immune system

abnormal osteoclast physiology ( J:378753 )

• mice exhibit reduced osteogenic potential accompanied by impaired osteoclast localization and activity during PF suture remodeling

hematopoietic system

abnormal osteoclast physiology ( J:378753 )

• mice exhibit reduced osteogenic potential accompanied by impaired osteoclast localization and activity during PF suture remodeling

growth/size/body

short nasal bone ( J:378753 )

• shortened nasal bones at P30

short snout ( J:378753 )

• shortened nose

respiratory system

short nasal bone ( J:378753 )

• shortened nasal bones at P30

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Frank-Ter Haar syndrome		DOID:0111789	OMIM:249420	J:378753

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

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

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

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