Molecular basis of cleft palates in mice

Table 1 Molecules involved in cleft palate in mice

Knockout mice with cleft palates			Humans
Gene/category	Protein	Ref.	OMIM	Syndrome	CL/P
Growth factors, antagonist, and receptors
Acvr1/Alk2	Activin A receptor, type I	[33]	1102576	Fibrodysplasia ossificans progressiva	nr
(Wnt1-Cre-mediated ablation)
Acvr2a	Activin A receptor, type IIA	[34]	1102581	nr	nr
Bmp4	Bone morphogenetic protein 4	[35]	1112262	Microphthalmia, syndromic 6	r
				Orofacial cleft 11
Bmp7	Bone morphogenetic protein 7	[36]	1112267	nr	nr
Bmpr1a/Alk3	Bone morphogenetic protein receptor, type IA	[35]	1601299	Juvenile polyposis syndrome,	nr
(Nestin-Cre-mediated ablation)				Polyposis syndrome
Chrd	Chordin	[37]	1603475	nr	nr
Ctgf	Connective tissue growth factor	[38]	1121009	nr	nr
Edn1	Endothelin 1	[39]	2131240	Auriculocondylar syndrome 3	r
Egfr	Epidermal growth factor receptor	[17]	1131550	nr	nr
Fgf9	Fibroblast growth factor 9	[40]	1600921	uc	nr
Fgf10	Fibroblast growth factor 10	[13,41]	1602115	Aplasia of lacrimal and salivary glands	nr
				LADD syndrome
Fgf18	Fibroblast growth factor 18	[42,43]	1603726	nr	nr
Fgfr1	Fibroblast growth factor receptor 1	[44]	1136350	Nonsyndromic cleft lip/palate	r
				Hartsfield syndrome
				Hypogonadotropic hypogonadism 2
				Pfeiffer syndrome
Fgfr2	Fibroblast growth factor receptor 2	[13,45]	1176943	Apert syndrome	r
(knockout) (Krt14-Cre-mediated ablation)				Crouzon syndrome
				Pfeiffer syndrome
				Saethre-Chotzen syndrome
Fst	Follistatin	[46]	1136470	nr	nr
Gabrb3	Gamma-aminobutyric acid A receptor, beta 3	[47]	1137192	Epilepsy, childhood absence, susceptibility to, 5	r
Gdf11/Bmp11	Growth differentiation factor 11	[48]	1603936	nr	nr
Gpr124	G protein-coupled receptor 124	[49]	1606823	nr	nr
Inhba	Inhibin, beta A/activin A	[50]	1147290	nr	nr
Pdgfc	Platelet-derived growth factor C	[51]	1608452	nr	r [52]
Pdgfra	Platelet-derived growth factor receptor, alpha polypeptide	[53,54]	1173490	Gastrointestinal stromal tumor, somatic	r
(knockout) (Wnt1-Cre-mediated ablation)				Hypereosinophilic syndrome, idiopathic, resistant to imatinib
Tgfb2	Transforming growth factor, beta 2	[55]	1190220	Loeys-Dietz syndrome, type 4	r
Tgfb3	Transforming growth factor, beta 3	[15,16,18]	1190230	Arrhythmogenic right ventricular dysplasia 1	r
Tgfbr1/Alk5	Transforming growth factor, beta receptor I	[56,57]	1190181	Loeys-Dietz syndrome, type 1	r
(Wnt1-Cre-, and Nestin-Cre-mediated ablation)
Tgfbr2	Transforming growth factor, beta receptor II	[12,58]	1190182	Loeys-Dietz syndrome, type 2	r
(Wnt1-Cre-, and KRT14-Cre-mediated ablation)
Vegfa	Vascular endothelial growth factor A	[59]	2192240	nr	nr
Membrane proteins
Ceacam1	Carcinoembryonic antigen-related cell adhesion molecule 1	[60]	1109770	nr	nr
Efna5	Ephrin A5	[61]	1601535	nr	nr
Efnb1	Ephrin B1	[62]	1300035	Craniofrontonasal dysplasia	r
Efnb2	Ephrin B2	[63]	1600527	nr	nr
Fzd2	Frizzled class receptor 2	[64]	1600667	nr	nr
Itga5	Integrin alpha 5	[65,66]	1135620	nr	nr
(knockout) (Mesp1-Cre-mediated ablation)
Itgb1	Integrin beta 1	[67]	1135630	nr	nr
(Col2a1-Cre-mediated ablation)
Itgb8	Integrin beta 8	[68]	1604160	nr	nr
Jag1	Jagged1	[69]	2601920	Alagille syndrome	nr
(Wnt1-Cre-mediated ablation)
Jag2	Jagged2	[70]	1602570	nr	nr
Kcnj2	Potassium inwardly-rectifying channel, subfamily J, member 2	[71]	1600681	Andersen syndrome	r
				Atrial fibrillation, familial, 9
				Short QT syndrome 3
Lrp6	Low density lipoprotein receptor-related protein 6	[72]	1603507	nr	nr
Ror2	Receptor tyrosine kinase-like orphan receptor 2	[73]	1602337	Robinow syndrome, autosomal recessive	r
				Brachydactyly, type B1
Ryk	Receptor-like tyrosine kinase	[74]	1600524	nr	nr
Ryr1	Ryanodine receptor 1, skeletal muscle	[75]	1180901	Central core disease	nr
				King-Denborough syndrome
				Minicore myopathy with external ophthalmoplegia
Sc5d/Sc5dl	Sterol-C5-desaturase (fungal ERG3, delta-5-desaturase) homolog (S. cerevisae)	[76]	1602286	Lathosterolosis	nr
Shh	Sonic hedgehog	[13,77]	1600725	Holoprosencephaly-3	r
(KRT14-Cre-, and Sox2-Cre-mediated ablation)				Microphthalmia with coloboma 5
				Single median maxillary central incisor
Smo/Smoh	Smoothened, frizzled class receptor	[78]	1601500	Basal cell carcinoma, somatic	nr
(Wnt1-Cre-mediated ablation)
Tctn2	Tectonic family member 2	[79]	1613846	Meckel syndrome 8	r
Wls/Gpr177	Wntless homolog (Drosophila)	[80]	1611514	nr	nr
(Wnt1-Cre-mediated ablation)
Wnt5a	Wingless-type MMTV integration site family, member 5A	[81]	1164975	Robinow syndrome, autosomal dominant	r
Wnt9b	Wingless-type MMTV integration site family, member 9B	[82,83]	1602864	nr	nr
(knockout) (Foxg1-Cre-mediated ablation)
Transcription and nucleolar factors
Alx1	Aristaless-like homeobox 1	[84]	1601527	Frontonasal dysplasia 3	r
Alx3	Aristaless-like homeobox 3	[85]	1606014	Frontonasal dysplasia 1	r
Alx4	Aristaless-like homeobox 4	[85]	1605420	Frontonasal dysplasia 2	Cleft alae nasi
				Parietal foramina 2
				Craniosynostosis 5
Anp32b	Acidic (leucine-rich) nuclear phosphoprotein 32 family, member B	[86]	nr	nr	nr
Arid5	AT-rich interaction domain-containing protein 5A	[87]	1611583	nr	nr
Asxl1	Additional sex combs like 1	[88]	1612990	Bohring-Opitz syndrome	r
				Myelodysplastic syndrome, somatic
Barx1	BarH-like homeobox 1	[89]	1603260	nr	nr
Cdc42	Cell division cycle 42	[90]	1116952	nr	nr
(Prrx1-Cre-mediated ablation)
Chd7	Chromodomain helicase DNA binding protein 7	[91,92]	1608892	CHARGE syndrome	r
(heterozygotes) (Wnt1-Cre-mediated ablation)				Hypogonadotropic hypogonadism 5 with or without anosmia
Cited2	CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2	[93]	1602937	Atrial septal defect 8	nr
				Ventricular septal defect 2
Crebbp/Cbp	CREB binding protein	[94]	1600140	Rubinstein-Taybi syndrome	nr
Dlx1	Distal-less homeobox 1	[95]	1600029	nr	nr
Dlx2	Distal-less homeobox 2	[95]	1126255	nr	nr
Dlx5	Distal-less homeobox 5	[96,97]	1600028	Split-hand/foot malformation 1 with sensorineural hearing loss	r
Dph1/Ovca1	DPH1 homolog (S. cerevisiae)	[98]	1603527	nr	nr
Eya1	Eyes absent 1 homolog (Drosophila)	[99]	1601653	Branchiootic syndrome 1	r
				Branchiootorenal syndrome 1, with or without cataracts
				Anterior segment anomalies with or without cataract
Foxc2/Mfh1	Forkhead box C2	[100]	1602402	Lymphedema-distichiasis syndrome	r
Foxd3	Forkhead box D3	[101]	1611539	uc	nr
(Wnt1-Cre-mediated ablation)
Foxe1/Titf2/Fkhl15	Forkhead box E1	[102]	1602617	Bamforth-Lazarus syndrome	r
				Nonsyndromic orofacial clefting
Foxf2	Forkhead box F2	[103]	1603250	nr	nr
Gbx2	Gastrulation brain homeobox 2	[104]	1601135	nr	nr
Gli2	GLI family zinc finger 2	[8]	1165230	Culler-Jones syndrome	r
				Holoprosencephaly-9
Gli3	GLI family zinc finger 3	[105]	1165240	Greig cephalopolysyndactyly syndrome	r
				Pallister-Hall syndrome
Gsc	Goosecoid homeobox	[106]	1138890	Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities	nr
Hand2/dHand	Heart and neural crest derivatives expressed 2	[107]	1602407	nr	nr
Hic1	Hypermethylated in cancer 1	[108]	1603825	nr	nr
Hoxa2	Homeobox A2	[19]	1604685	Microtia with or without hearing impairment (AD)	r
				Microtia, hearing impairment, and cleft palate (AR)
Irf6	Interferon regulatory factor 6	[109,110]	1607199	van der Woude syndrome	r
				Orofacial cleft 6
				Popliteal pterygium syndrome 1
Jmjd6/Ptdsr	Jumonji domain containing 6	[111]	1604914	nr	nr
Kat6a/Moz/Myst3	K (lysine) Acetyltransferase 6A	[112]	1601408	nr	nr
Lhx7	LIM homeobox gene 7	[113]	nr	nr	nr
Lhx8	LIM homeobox gene 8	[11]	1604425	nr	r
Luzp1	Leucine zipper protein 1	[114]	1601422	nr	nr
Mef2c	MADS box transcription enhancer factor 2	[115]	1600662	Chromosome 5q14.3 deletion syndrome	nr
(Wnt1-Cre-mediated ablation)				Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations
Meox2	Mesenchyme homeobox 2	[116]	1600535	nr	nr
Mn1	Meningioma 1	[117]	1156100	Meningioma	nr
Mnt	Max binding protein	[118]	1603039	nr	nr
Msx1	Msh homeobox 1	[10,23]	1142983	Ectodermal dysplasia 3, Witkop type	r
				Orofacial cleft 5
				Tooth agenesis, selective, 1, with or without orofacial cleft
Msx2	Msh homeobox 2	[119]	1123101	Craniosynostosis, type 2	r
(missense mutation)				Parietal foramina 1
				Parietal foramina with cleidocranial dysplasia
Nabp2/Obfc2b/hSSB1	Nucleic acid binding protein 2	[120,121]	1612104	nr	nr
Osr2	Odd-skipped related transcription factor 2	[9]	1611297	nr	r
Pak1ip1	PAK1 interacting protein 1	[122]	1607811	nr	nr
Pax9	Paired box gene 9	[6]	1167416	Tooth agenesis, selective, 3	nr
Pbx1	Pre B cell leukemia homeobox 1	[83]	1176310	Leukemia, acute pre-B-cell	nr
Pds5a	PDS5, regulator of cohesion maintenance, homolog A (S. cerevisiae)	[123]	1613200	nr	nr
Phc1/Rae28	Polyhomeotic homolog 1	[124]	1602978	uc	nr
Pitx1	Paired-like homeodomain 1	[7,125]	1602149	Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly	r
				Liebenberg syndrome
Pitx2	Paired-like homeodomain 2	[126]	1601542	Axenfeld-Rieger syndrome, type 1	nr
				Iridogoniodysgenesis, type 2
				Peters anomaly
Pnn	Pinin	[127]	1603154	nr	nr
Prdm16	PR domain containing 16	[128]	1605557	Cardiomyopathy, dilated, 1LL	nr
				Left ventricular noncompaction 8
Prrx1/Prx1/Mhox	Paired related homeobox 1	[129]	1167420	Agnathia-otocephaly complex	r
Ptch1/Ptc1	Patched 1	[130]	1601309	Basal cell nevus syndrome	r
(Wnt1-Cre-mediated ablation)				(Gorlin syndrome)
				Holoprosencephaly type 7
Pygo2	Pygopus 2	[131]	1606903	nr	nr
(CMV-Cre-mediated ablation)
Rax	Retina and anterior neural fold homeobox	[132]	1601881	Microphthalmia, isolated 3	nr
Recql4	RecQ protein-like 4	[133]	1603780	Baller-Gerold syndrome	r
				RAPADILINO syndrome
				Rothmund-Thomson syndrome
Runx2	Runt-related transcription factor 2	[134]	1600211	Cleidocranial dysplasia	r
Sall3	Spalt-like transcription factor 3	[24]	1605079	nr	nr
Satb2	SATB homeobox 2	[135,136]	1608148	Glass syndrome	r
Shox2	Short stature homeobox 2	[22]	1602504	nr	nr
Sim2	Single-minded family bHLH transcription factor 2	[137]	1600892	nr	nr
Smad4 (Osr2-Cre-mediated ablation)	SMAD family member 4	[138]	1600993	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	nr
				Myhre syndrome
Smad7	SMAD family member 7	[139]	1602932	uc	nr
Snai2	Snail family zinc finger 2	[140]	1602150	Piebaldism	nr
				Waardenburg syndrome, type 2D
Sox5	SRY (sex determining region Y)-box 5	[141]	1604975	nr	nr
Sox9 (heterozygous)	SRY (sex determining region Y)-box 9	[142,143]	1608160	Acampomelic campomelic dysplasia	r
(Wnt1-Cre-mediated ablation)
Sox11	SRY (sex determining region Y)-box 11	[144]	1600898	Mental retardation, autosomal dominant, 27	nr
Sp8	Sp8 transcription factor	[145]	1608306	nr	nr
Tshz1	Teashirt zinc finger family member 1	[146]	1614427	Aural atresia, congenital	nr
Tbx1	T-box 1	[4,147]	1602054	DiGeorge syndrome	r
(knockout) (KRT14-Cre-mediated ablation)				Velocardiofacial syndrome
				Conotruncal anomaly face syndrome
				Tetralogy of Fallot
Tbx2	T-box 2	[148]	1600747	nr	nr
Tbx22	T-box 22	[149]	1300307	Cleft palate with ankyloglossia	r
				submucous cleft palate (SMCP)
Tcof1	Treacher Collins-Franceschetti syndrome 1	[150]	1606847	Treacher-Collins syndrome	r
(heterozygous)
Tfap2A	Transcription factor AP-2 alpha	[151]	1107580	Branchio-oculo-facial syndrome	r
(Wnt1-Cre-mediated ablation)
Trp63/Tp63	Transformation related protein p63	[152]	1603273	Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3	r
				Orofacial cleft 8
				Hay-Wells syndrome
				Limb-mammary syndrome
Vax1	Ventral anterior homeobox 1	[153]	1604294	Microphthalmia, syndromic 11	r
Whsc1	Wolf-Hirschhorn syndrome candidate 1	[154]	1602952	nr	nr
Zeb1	Zinc finger E-box binding homeobox 1	[155]	1189909	Corneal dystrophy	nr
Zfp640/Mzf6d	Zinc finger protein 640	[87]	nr	nr	nr
Zic3	Zinc finger protein of the cerebellum 3	[156]	1300265	Congenital heart defects, nonsyndromic	r
				Heterotaxy, visceral, 1
				VACTERL association
Cytoplasmic proteins
Akap8/Akap95	A kinase (PRKA) anchor protein 8	[157]	1604692	nr	nr
Apaf1	Apoptotic peptidase activating factor 1	[158]	1602233	nr	nr
B9d1	B9 protein domain 1	[159]	1614144	Meckel syndrome 9	nr
Cask	Calcium/calmodulin-dependent serine protein kinase	[160]	1300172	FG syndrome 4	r
				Mental retardation and microcephaly with pontine and cerebellar hypoplasia
Cdkn1c/p57kip2	Cyclin-dependent kinase inhibitor 1C	[161,162]	1600856	Beckwith-Wiedemann syndrome	r
				IMAGe syndrome
Chuk/Ikk1/Tcf16	Conserved helix-loop-helix ubiquitous kinase	[163]	1600664	Cocoon syndrome	nr
Crk	v-crk sarcoma virus CT10 oncogene homolog	[164]	1164762	nr	nr
Ctnnb1	Catenin (cadherin-associated protein), beta 1,	[165,166]	1116806	Mental retardation, autosomal dominant 19	nr
(KRT14-Cre-mediated ablation)
Cyp26B1	Cytochrome P450, family 26, subfamily b, polypeptide 1	[167]	1605207	Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies	nr
Cyp51	Cytochrome P450, family 51	[168]	1601637	nr	nr
Dhcr7	7-dehydrocholesterol reductase	[169,170]	1602858	Smith-Lemli-Opitz syndrome	r
Dhrs3	Dehydrogenase/reductase (SDR family) member 3	[171,172]	1612830	nr	nr
Dicer1	Dicer 1, ribonuclease type III	[29]	1606241	Rhabdomyosarcoma, embryonal, 2	nr
(Pax2-Cre-mediated ablation)				Goiter, multinodular 1
				Pleuropulmonary blastoma
Dlg1/Dlgh/Sap97	Discs large 1	[173]	1601014	nr	nr
Fuz	Fuzzy planar cell polarity protein	[174]	1610622	Neural tube defects	nr
Gab1	Growth factor receptor bound protein 2-associated protein 1	[175]	1604439	nr	nr
Gad1/Gad67	Glutamate decarboxylase 1	[176,177]	1605363	Cerebral palsy, spastic quadriplegic, 1	r
Glce	Glucuronyl C5-epimerase	[178]	1612134	nr	nr
Glg1	Golgi apparatus protein 1	[179]	1600753	nr	nr
Grb2	Growth factor receptor bound protein 2	[180]	1108355	nr	nr
Gsk3b	Glycogen synthase kinase 3 beta	[181]	1605004	nr	nr
Hs2st1	Heparan sulfate 2-O-sulfotransferase 1	[182]	1604844	nr	nr
Hspb11/Ift25	Heat shock protein family B (small), member 11	[183]	1604844	nr	nr
Ilk	Integrin linked kinase	[184]	1602366	nr	nr
(Col2a1-Cre-mediated ablation)
Impad1/Jaws	Inositol monophosphatase domain containing 1	[185]	1614010	Chondrodysplasia with joint dislocations, GRAPP type	r
Inpp5e	Inositol polyphosphate-5-phosphatase E	[186]	1613037	Joubert syndrome 1	nr
				Mental retardation, truncal obesity, retinal dystrophy, and micropenis
Kif3a	Kinesin family member 3A	[187]	1604683	nr	nr
(Wnt1-Cre-mediated ablation)
Map3k7/Tak1	Mitogen-activated protein kinase kinase kinase 7	[188,189]	1602614	nr	nr
(Wnt1-Cre-mediated ablation)
Nprl3	Nitrogen permease regulator-like 3	[190]	1600928	nr	nr
Ofd1	Oral-facial-digital syndrome 1 gene homolog (human)	[191]	1300170	Joubert syndrome 10	r
(CAG-Cre-mediated ablation)				Orofaciodigital syndrome I
				Simpson-Golabi-Behmel syndrome, type 2
Pdss2	Prenyl (solanesyl) diphosphate synthase, subunit 2	[192]	1610564	Coenzyme Q10 deficiency, primary, 3	nr
(Pax2-Cre-mediated ablation)
Piga	Phosphatidylinositol glycan anchor biosynthesis, class A	[193]	1311770	Multiple congenital anomalies-hypotonia-seizures syndrome 2 Paroxysmal nocturnal hemoglobinuria, somatic	nr
(EIIa-Cre-mediated ablation)
Pkdcc/Vlk	Protein kinase domain containing, cytoplasmic	[194,195]	1614150	nr	nr
(Sox2-Cre-mediated ablation)
Prickle1	Prickle homolog 1	[196]	1608500	Epilepsy, progressive myoclonic 1B	nr
Rad23b	RAD23b homolog (S. cerevisiae)	[197]	1600062	nr	nr
Rspo2	R-spondin 2 homolog (Xenopus laevis)	[198,199]	1610575	nr	nr
Schip1	Schwannomin interacting protein 1	[87]	nr	nr	nr
Sdccag8	Serologically defined colon cancer antigen 8	[200]	1613524	Bardet-Biedl syndrome 16	nr
				Senior-Loken syndrome 7
Slc32a1/Viaat	Solute carrier family 32, member 1	[201,202]	nr	nr	nr
Spry1	Sprouty homolog 1	[203]	1602465	nr	nr
(Wnt1-Cre-mediated ablation)
Spry2	Sprouty homolog 2	[204]	1602466	nr	nr
Sumo1	SMT3 suppressor of mif two 3 homolog 1 (yeast)	[205]	1601912	Orofacial cleft 10	r
(heterozygous)
Ugdh	UDP-glucose dehydrogenase	[206]	1603370	nr	nr
(Wnt1-Cre-mediated ablation)
Wdpcp	WD repeat containing planar cell polarity effector	[207]	1613580	uc	nr
Extracellular proteins
Col2a1	Collagen, type II, alpha 1	[208]	2120140	Achondrogenesis, type II	r
				Stickler syndrome, type I
				Kniest dysplasia
Hspg2	Heparan sulfate proteoglycan 2, perlecan	[209,210]	1142461	Dyssegmental dysplasia	nr
				Schwartz-Jampel syndrome, type 1
Serpinh1/Hsp47	Serpine peptidase inhibitor, clade H, member 1	[211]	1600943	Osteogenesis imperfecta, type X	nr
(Col2a1-Cre-mediated ablation)
Smoc1	SPARC related modular calcium binding 1	[212]	1608488	Microphthalmia with limb anomalies	r

¹Before an OMIM entry number indicates a gene;

²Before an OMIM entry number indicates that the entry includes a description of a gene of known sequence and a phenotype. OMIM: Online Mendelian Inheritance in Man (http://omim.org); CL/P: Cleft lip and/or palate; r: Reported; nr: Not reported; uc: Unclarified.