Table 5

Symbol

Targeted Gene

Phenotype details

References

Map Pos.

J:39394

53.0

J:29456 J:29457

12.5

reduced beta-oxidation of very long chain fatty acids Lu et al. (1997) PNAS USA 94: 9366-9371; X-linked adrenoleukodystrophy (VLCFAs) with consequent elevation of saturated VLCFAs in ForssPetter et al. (1997) J. Neurosci. Res. 50: 829-

J:42479 J:44812

29.5

Bgn

biglycan

skeletal phenotype marked by progressive lowering of bone Xu et al.(1998) Nature Genetics 20: 78-82 mass, suggested model for role of ECM proteins in osteoporosis

J:49647

29.3

Brs3

bombesin receptor subtype-3

mild obesity, hypertension, impaired glucose metabolism, reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia

J:44242

Btk

mild X-linked immunodeficiency, with additional compromise Kerner et al. (1995) Immunity 3: 301-312; of B cell precursor expansion Khan et al. (1997) Int. Immunol. 9: 395-405

Cd40l

Bruton agammaglobulinemia tyrosine kinase(=xid) CD40 antigen ligand

Cf8

coagulation factor VIII

Cf9

coagulation factor IX

<1% factor VIII clotting activity, significant bleeding after tail biopsy which may be lethal, no spontaneous bleeding absence of factor IX antigen in plasma, <5% factor IX clotting Wang et al. (1997) PNAS USA 94: 11563-11566 activity

Cybb

subunit of NADPHoxidase complex

chronic granulomatous disease(CGD), lack phagocyte superoxide production, increased susceptibility to infection and altered inflammatory response to thioglycollate peritonitis

Pollock et al. (1995) Nature Genetics 9: 202-209; J:22868 Morgenstern et al. (1997) J. Exp. Med. 185: 207-218 Medline 97169063

Dmd

dystrophin, muscular dystrophy

hypertrophic skeletal muscles, fibre size variations with necrosis and regeneration

Araki et al. (1997) Biochem. Biophys. Res. Comm. 238: 492-497

Ags

alpha galactosidase

Agtr2

angiotensin II receptor, type 2

Aldgh

clinically normal at 10 weeks, complete absence of alpha-Gal Ohshima et al. (1997) PNAS USA 94: 2540-2544 A activity, examination of liver and kidney revealed similar pathophysiology to human Fabry disease blood pressure increase, increased sensitivity to pressor Hein et al. (1995) Nature 377: 744-747; action of angiotensin II, lowered body temperature and Ichiki et al. (1995) Nature 377: 748-750 reduced exploratory behaviour

Ref. ID

total lipids of all tissues and cholesterol esters in 843 adrenocortical cells, but no neurological involvement seen in mice up to 6 months

failure to undergo isotype switching to T-cell-dependent antigens, normal response to T-cell-independent antigens

Ohki-Hamazaki et al. (1997) Nature 390: 165-169

J:28967 Medline 97244169

51.0

Castigli et al. (1995) Int. Arch. Allergy Immunol. 107: Medline 37-39; Xu et al. (1994) Immunity 1: 423-231; 95337793 Renshaw et al. (1994) J. Exp. Med. 180: 1880-1900. J:25010 J:21137 Bi et al. (1995) Nature Genetics 10: 119-121 J:24941

18.0

J:43590

J:43164

30.5 22.0 2.8

32.0

Cask

Ca2+ dependent protein kinase

cleft secondary palate, neonatal male lethality, suggested model for human X-linked cleft secondary palate syndrome

Fmr1

fragile X mental retardation syndrome 1 homologue glucose-6-phosphate dehydrogenase

Macroorchidism, learning deficits, hyperactivity and lack of normal Fmr1 protein

G6pdx

at ES cell level only, clones with undetectable levels of the enzyme are extremely sensitive to hydrogen peroxide and diamide

Wilson et al. (1993) Cell Growth & Diff. 4: 67-76; Laverty and Wilson (1998) Genomics 53: 29-41 Bakker et al. (1994) Cell 78: 23-33; Oostra and Hoogeveen et al. (1997) Annals of Medicine 29: 563-567

J:18214

5.0

J:19220 J:47489

24.5

Pandolfi et al. (1995) EMBO J. 14: 5209-5215

Medline 96080156

Gata1

GATA-binding protein 1 male neonatal lethal, mid-gestation embryos pallid with

Pevny et al. (19910 Nature 349: 257-260; Fujiwara et al. (1996) PNAS USA 93: 12355-12358; Takahashi et al. (1997) J. Biol. Chem. 272: 1261112615 from 3 months progressive demyelinating neuropathy, motor Scherer et al. (1998) Glia 24: 8-20 fibres more affected than sensory fibres, model for CharcotMarie-Tooth disease?

J:36462 J:36249 J:40321

Gjb1

gap junction protein connexin32

Medline 98365842

Gpc3 Grpr

glypican 3 gastrin releasing peptide receptor

Gyk

glycerol kinase

Hprt

hypoxanthine phosphoribosyltransferase

Htr2c

overweight because of abnormal feeding behaviour, 5-hydroxytryptamine (serotonin) receptor 2C spontaneous death from seizures

Tecott et al. (1995) Nature 374: 542-546

Il2rg

interleukin 2 receptor, gamma chain

similar phenotype to human XSCID, decrease in lymphocyte Leonard et al. (1995) Immunol. Rev. 148: 97-114; numbers but increase in monocytes, few T cells in young Sugamura et al. (1996) Ann. Rev. Immunol. 14: 179mice and no natural killer cells 205; Ohbo et al. (1996) Blood 87: 956-967

L1cam

L1 cell adhesion molecule

smaller than wild type animals, uncoordinated hind legs, hypoplasia of corticospinal tract, abnormal brain pathology, and impaired exploratory behaviour

Medline 96422667 Medline 96292426 J:31167 Dahme et al. (1997) Nature Genetics 17: 346-349; J:43838 Fransen et al. (1998) Hum. Mol. Genet. 7: 999-1009 J:47995

arrest of erythroid development

Li et al. (1998) Clin. Genet. 53: 165-170

30.02

2.1

38.0

J:47826

syntenic

no gross phenotypic abnormalities, but bombesin ineffective Hampton et al. (1998) PNAS USA 95: 3188-3192 at suppress glucose intake

J:46897

70.0

males normal at birth but exhibit growth retardation, altered Huq et al. (1997) Hum. Mol. Genet. 11: 1803-1809 fat metabolism with profound hypoglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis and death by 3-4 days. Heterozygous females are healthy and biochemically normal none unless Aprt also eliminated (Wu and Melton (1993) Hooper et al. (1987) Nature 326: 292-295; Nature Genet. 3: 235-240) Kuehn et al. (1987) Nature 326: 295-298; Nehls et al. (1994) Biotechniques 17: 770-775; Tsuda et al. (1997) Genomics 42:413-421

J:43449

33.0

J:15483 J:15485 Medline 95134423 J:41459

17.0

J:24339

66.15

38.0

29.51

Maoa

monoamine oxidase a pups had elevated serotonin levels, trembling, difficulty in

J:26232

5.2

Maob

monoamine oxidase b

J:43648

5.2

Mecp2

methyl CpG binding protein 2 murine p55

Cases et al. (1995) Science 268: 1763-1766 righting and fearfulness, adults had distinct behavioural syndrome with enhanced aggression in males increased reactivity to stress, increased levels of betaGrimsby et al. (1997) Nature Genetics 17: 206-210 phenylethylamine, resistance to neurodegenerative effects of MPTP toxin (which induces a Parkinson's like condition) chimareic embryos exhibited developmental defects with Tate et al. (1996) Nature Genetics 12: 205-208 severity proportional to mutant cell contributions

J:31573

29.6

meeting abstract

IS 10591524 J:30902

30.48

Mpp1

Kim et al. (1996) Mol. Biol. of the Cell 7: 999

Ndph

Norrie disease homologue

development of retrolental structures in vitreous body, Berger et al. (1996) Hum. Mol. Genet. 5: 51-59 disorganisation of retinal ganglion cell layer, occasional loss of outer plexiform layer with resultant interchange of inner/outer nuclear layer, absence of outer segments of photoreceptor cell layer

Ocrl

oculocerebrorenal syndrome of Lowe

no abnormal phenotype, with postulated compensation by the autosomal gene inositol polyphosphate 5-phosphatase (Inpp5b) as explanation

Janne et al. (1998) J. Clin. Invest. 101: 2042-2053

J:47884

syntenic

Piga

phosphatidylinositol glycan, class A

wrinkled and scaly skin, death a few days after birth

Tarutani et al. (1997) PNAS USA 94: 7400-7405

J:41746

67.0

Plp

myelin proteolipid protein(=DXNds2, DXMit9, jimpy)

no gross effect, assembly and maintenance of normal amounts of myelin, progressive tract-specific axonopathy notes: (1) correction of natural mutant with wild type transgene not possible (2) over expression has more severe clinical effects

Boison and Stoffel (1994) PNAS USA 91: 11709J:21976 11713; Griffiths et al. (1995) Brain Pathol. 5: 275-281; J:31051 Klugmann et al. (1997) Neuron 18: 59-70; J:38856 Griffiths et al. (1998) Microsc. Res. Tech. 41: 344-358 Medline 98336162

56.0

Pou3f4 Pou domain, class 3, transcription factor 4

vertical head bobbing and hearing loss, dysplastic bony compartment of the inner ear

Crenshaw et al.( 1998) Heredity Deafness Newsletter J:32903 15: 46; Ikeda et al. (1998) Heredity Deafness J:48665 Newsletter 15: 47-48

49.0

Pou4f2 POU domain,class 4, transcription factor 2

selective loss of 70% of retinal ganglion cells, but other neurons in the retina and brain essentially unaffected

Gan et al. (1996) PNAS USA 93: 3920-3925; Erkman et al. (1996) Nature 381: 603-606

Rep1

embryonic male lethal; heterozygous females and chimeras van den Hurk et al (1997) Hum. Mol. Genet. 6: 851have a variable number of photoreceptor cells 858

J:40673

syntenic

no gross abnormalities, mossy fibre giant terminals reduced, Rosahl et al. (1993) Cell 75: 661-670; fewer synaptic vesicles, and presynaptic structures altered Takei et al. (1995) J. Cell Bio. 131: 1789-1800

J:15701 J:30400

6.2

Syn1

Rab escort protein 1, (mutated in choroideraemia) synapsin 1

5.3

syntenic

Syp

synaptophysin

Timp

tissue inhibitor of metalloproteinase

Arrandale et al. (1996) J. Biol. Chem. 271: 21353J:35137; 1.7 21358; Chin et al. (1995) PNAS USA 92: 9230-9234; J:29085 Eshkind and Leube (1995) Cell Tissue Res. 282: J:30488 423-433; J:33035 McMahon et al. (1996) PNAS USA 93: 4760-4764 no effect on steroidogenesis, reduced ovarian TIMP2 and Nothnick et al. (1997) Bio. Reprod. 56: 1181-1188; J; 40265 Medline6.2 92348514 TIMP3, at ES cell level only, more invasive than normal cells Alexander and Werb (1992) J. Cell Biol. 118: 727-739

Wasp

Wiskott-Aldrich syndrome protein

decreased peripheral blood lymphocyte and platelet numbers, chronic colitis

Snapper et al. (1998) Immunity 9: 81-91

J:48836

2.1

Xist

inactive X specific transcripts

mutant males inaffected, females inheriting mutant paternal X chromosome severely retarded and die in utero

Marahens et al. (1997) Genes Dev. 11: 156-166

J:38094

42.0

Xnp

X-linked nuclear protein at cellular level, increased sensitivity to ionising radiation,

Essers et al. (1997) Cell 89: 195-204

J:39642

43.8

Zfx

X-linked zinc finger protein

J:41131

34.6

indistinguishable from normal littermates, predendritic neurites and axon outgrowth retarded in hippocampal neurons, with delayed synapse formation; homozygotes die prior to 10.5 dpc

mitomycin C and methyl methanesulphonate

male and female mutants smaller. with lowere viability and fewer germ cells, hemizygotes had reduced sperm count and homozygotes a reduced number of oocytes Luoh et al. (1997) 124: 22275-2284

Different ref. format

TARGETED DISRUPTION OF X-LINKED G Symbol Targeted Gene alpha galactosidase Ags Agtr2 Aldgh

Bgn Brs3 Btk Cd40l Cf8 Cf9

coagulation factor IX

Chm

mouse Choroideremia

Cybb

subunit of NADPHoxidase complex

Dmd DXRib1 Fmr1 G6pdx Gata1

Phenotype details

clinically normal at 10 weeks, complete absence of alpha-Gal A activity, examination of liver and kidney revealed similar pathophysiology to human Fabry disease angiotensin II receptor, blood pressure increase, increased sensitivity to pressor action type 2 of angiotensin II, lowered body temperature and reduced exploratory behaviour X-linked reduced beta-oxidation of very long chain fatty acids (VLCFAs) adrenoleukodystrophy with consequent elevation of saturated VLCFAs in total lipids of all tissues and cholesterol esters in adrenocortical cells, but no neurological involvement seen in mice up to 6 months skeletal phenotype marked by progressive lowering of bone biglycan mass, suggested model for role of ECM proteins in osteoporosis bombesin receptor mild obesity, hypertension, impaired glucose metabolism, subtype-3 reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia Bruton mild X-linked immunodeficiency, with additional compromise of agammaglobulinemia B cell precursor expansion tyrosine kinase(=xid) failure to undergo isotype switching to T-cell-dependent CD40 antigen ligand antigens, normal response to T-cell-independent antigens coagulation factor VIII absence of factor IX antigen in plasma, model for haemophilia B embryonic male lethal

chronic granulomatous disease(CGD), lack phagocyte superoxide production, increased susceptibility to infection and altered inflammatory response to thioglycollate peritonitis dystrophin, muscular hypertrophic skeletal muscles, fibre size variations with dystrophy necrosis and regeneration fortuitous transgenic cleft secondary palate, neonatal male lethality, suggested insertion in locus model for human X-linked cleft secondary palate syndrome fragile X mental Macroorchidism, learning deficits, hyperactivity and lack of retardation syndrome 1 normal Fmr1 protein homologue glucose-6-phosphate at ES cell level only, clones with undetectable levels of the dehydrogenase enzyme are extremely sensitive to hydrogen peroxide and diamide GATA-binding protein 1 male neonatal lethal, mid-gestation embryos pallid with arrest of erythroid development

Gjb1

gap junction protein connexin32

Gpc3 Grpr

glypican 3 gastrin releasing peptide receptor

from 3 months progressive demyelinating neuropathy, motor fibres more affected than sensory fibres, model for CharcotMarie-Tooth disease? no gross phenotypic abnormalities, but bombesin ineffective at suppress glucose intake

Page 5

Different ref. format

Gyk

glycerol kinase

Hprt

hypoxanthine phosphoribosyltransferase

Htr2c

5-hydroxytryptamine (serotonin) receptor 2C interleukin 2 receptor, gamma chain

overweight because of abnormal feeding behaviour, spontaneous death from seizures similar phenotype to human XSCID, decrease in lymphocyte numbers but increase in monocytes, few T cells in young mice and no natural killer cells

L1cam

L1 cell adhesion molecule

Maoa

monoamine oxidase A

smaller than wt animals, uncoordinated hind legs, hypoplasia of corticospinal tract, abnormal brain pathology, and impaired exploratory behaviour pups had elevated serotonin levels, trembling, difficulty in righting and fearfulness, adults had distinct behavioural syndrome with enhanced aggression in males

Mpp1 Ndph

murine p55

Ocrl

oculocerebrorenal syndrome of Lowe

Piga

phosphatidylinositol glycan, class A myelin proteolipid protein(=DXNds2, DXMit9, jimpy)

Il2rg

Plp

Norrie disease homologue

Syn1

POU domain,class 4, transcription factor 2 synapsin 1

Syp

synaptophysin

Timp

tissue inhibitor of metalloproteinase Wiskott-Aldrich syndrome protein X-linked nuclear protein

Pou4f2

Wasp Xnp

males normal at birth but exhibit growth retardation, altered fat metabolism with profound hypoglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis and death by 3-4 days. Heterozygous females are healthy and biochemically normal none unless Aprt also eliminated

development of retrolental structures in vitreous body, disorganisation of retinal ganglion cell layer, occasional loss of outer plexiform layer with resultant interchange of inner/outer nuclear layer, absence of outer segments of photoreceptor cell layer no abnormal phenotype, with postulated compensation by the autosomal gene inositol polyphosphate 5-phosphatase (Inpp5b) as explanation wrinkled and scaly skin, death a few days after birth assembly and maintenance of normal amounts of myelin, progressive tract-specific axonopathy notes: (1) correction of natural mutant with wild type transgene not possible (2) over expression has more severe clinical effects selective loss of 70% of retinal ganglion cells, but other neurons in the retina and brain essentially unaffected no gross abnormalities, mossy fibre giant terminals reduced, fewer synaptic vesicles, and presynaptic structures altered indistinguishable from normal littermates, predendritic neurites and axon outgrowth retarded in hippocampal neurons, with delayed synapse formation at ES cell level only, more invasive than normal cells decreased peripheral blood lymphocyte and platelet numbers, chronic colitis at cellular level, increased sensitivity to ionising radiation, mitomycin C and methyl methanesulphonate

Page 6

Different ref. format

OF X-LINKED GENES References

Posn.

J:39394:Ohshima et al. (1997) PNAS USA 94: 2540-2544

53.0

J:29456:Hein et al. (1995) Nature 377: 744-747; J:29457:Ichiki et al. (1995) Nature 377: 748-750

12.5

J:42479:Lu et al. (1997) PNAS USA 94: 9366-9371; J:44812:ForssPetter et al. (1997) J. Neurosci. Res. 50: 829-843

29.5

J:49647:Xu et al.(1998) Nature Genetics 20: 78-82

29.3

J:44242:Ohki-Hamazaki et al. (1997) Nature 390: 165-169 J:28967:Kerner et al. (1995) Immunity 3: 301-312; Medline 97244169:Khan et al. (1997) Int. Immunol. 9: 395-405

51.0

Medline 95337793:Castigli et al. (1995) Int. Arch. Allergy Immunol. 107: 37-39 J:24941:Bi et al. (1995) Nature Genetics 10: 119-121

18.0

J:43590:Wang et al. (1997) PNAS USA 94: 11563-11566

22.0

J:40673:van den Hurk et al (1997) Hum. Mol. Genet. 6: 851858 J:22868:Pollock et al. (1995) Nature Genetics 9: 202-209; Medline 97169063:Morgenstern et al. (1997) J. Exp. Med. 185: 207-218 J:43164:Araki et al. (1997) Biochem. Biophys. Res. Comm. 238: 492-497 J:18214:Wilson et al. (1993) Cell Growth & Diff. 4: 67-76

96.5

J:19220:Bakker et al. (1994) Cell 78: 23-33; J:47489:Oostra and Hoogeveen et al. (1997) Annals of Medicine 29: 563-567 Medline 96080156:Pandolfi et al. (1995) EMBO J. 14: 52095215

24.5

J:36249:Fujiwara et al. (1996) PNAS USA 93: 12355-12358; J:40321:Takahashi et al. (1997) J. Biol. Chem. 272: 1261112615 Medline 98365842:Scherer et al. (1998) Glia 24: 8-20 J:47826:Li et al. (1998) Clin. Genet. 53: 165-170

30.5

2.8 32.0 ?

30.02 2.1 38.0 ?

J:46897:Hampton et al. (1998) PNAS USA 95: 3188-3192

Page 7

70.0

Different ref. format

J:43449:Huq et al. (1997) Hum. Mol. Genet. 11: 1803-1809

33.0

J:15483:Hooper et al. (1987) Nature 326: 292-295; J:15485:Kuehn et al. (1987) Nature 326: 295-298; Medline 95134423:Nehls et al. (1994) Biotechniques 17: 770775; J:41459:Tsuda et al.(1997) Genomics 42:413-421 J:24339:Tecott et al. (1995) Nature 374: 542-546

17.0

Medline 96422667:Leonard et al. (1995) Immunol. Rev. 148: 97-114; Medline 96292426:Sugamura et al. (1996) Ann. Rev. Immunol. 14: 179-205; J:31167:Ohbo et al. (1996) Blood 87: 956-967 J:43838:Dahme et al. (1997) Nature Genetics 17: 346-349; J:47995:Fransen et al. (1998) Hum. Mol. Genet. 7: 999-1009 J:26232:Cases et al. (1995) Science 268: 1763-1766

66.15 38.0

29.51 5.2

IS 1059-1524:Kim et al. (1996) Mol. Biol. of the Cell 7: 999 J:30902:Berger et al. (1996) Hum. Mol. Genet. 5: 51-59

J:47884:Janne et al. (1998) J. Clin. Invest. 101: 2042-2053

30.48 5.3

?

J:41746:Tarutani et al. (1997) PNAS USA 94: 7400-7405

67.0

J;31051:Griffiths et al. (1995) Brain Pathol. 5: 275-281; J:38856:Klugmann et al. (1997) Neuron 18: 59-70; Medline 98336162:Griffiths et al. (1998) Microsc. Res. Tech. 41: 344-358 J:32903:Gan et al. (1996) PNAS USA 93: 3920-3925; J:33502:Erkman et al. (1996) Nature 381: 603-606 J:15701:Rosahl et al. (1993) Cell 75: 661-670; J:30400:Takei et al. (1995) J. Cell Bio. 131: 1789-1800 J:29085:Chin et al. (1995) PNAS USA 92: 9230-9234; J:30488:Eshkind and Leube (1995) Cell Tissue Res. 282: 423433; J:33035:McMahon et al. (1996) PNAS USA 93: 4760-4764 Medline 92348514:Alexander and Werb (1992) J. Cell Biol. 118: 727-739 J:48836:Snapper et al. (1998) Immunity 9: 81-91

56.0

J:39642:Essers et al. (1997) Cell 89: 195-204

43.8

Page 8

6.2 1.7

6.2 2.1