Phenotypic Mutation 'burrito' (pdf version)
Mutation Type missense
Coordinate20,451,862 bp (GRCm38)
Base Change T ⇒ A (forward strand)
Gene Dsg4
Gene Name desmoglein 4
Synonym(s) lah, CDHF13
Chromosomal Location 20,436,175-20,471,821 bp (+)
MGI Phenotype FUNCTION: This gene encodes a member of the cadherin family of proteins that forms an integral transmembrane component of desmosomes, the multiprotein complexes involved in cell adhesion, organization of the cytoskeleton, cell sorting and cell signaling. This gene is expressed in the suprabasal epidermis and hair follicle. The encoded preproprotein undergoes proteolytic processing to generate a mature, functional protein. Certain mutations in this gene are responsible for the lanceolate hair phenotype in mice. This gene is located in a cluster of desmosomal cadherin genes on chromosome 18. [provided by RefSeq, Feb 2016]
PHENOTYPE: Mice carrying mutations at this locus exhibit abnormalities in hair growth, vibrissae growth, and a thickened epidermis. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_181564; MGI:2661061

Amino Acid Change Valine changed to Glutamic Acid
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000019426]
AlphaFold Q7TMD7
SMART Domains Protein: ENSMUSP00000019426
Gene: ENSMUSG00000001804
AA Change: V211E

signal peptide 1 20 N/A INTRINSIC
CA 70 155 1.54e-11 SMART
CA 179 267 4.27e-19 SMART
CA 290 384 5.48e-8 SMART
CA 411 495 9.4e-7 SMART
transmembrane domain 634 656 N/A INTRINSIC
low complexity region 724 736 N/A INTRINSIC
Pfam:Cadherin_C 749 849 3.1e-8 PFAM
Predicted Effect possibly damaging

PolyPhen 2 Score 0.814 (Sensitivity: 0.84; Specificity: 0.93)
(Using ENSMUST00000019426)
Meta Mutation Damage Score 0.1795 question?
Is this an essential gene? Possibly nonessential (E-score: 0.450) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Alleles Listed at MGI

All Mutations and Alleles(8) : Chemically induced (ENU)(3) Spontaneous(2) Targeted(3)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00708:Dsg4 APN 18 20461326 missense probably benign 0.22
IGL01723:Dsg4 APN 18 20466510 missense probably damaging 1.00
IGL02249:Dsg4 APN 18 20461304 missense possibly damaging 0.69
IGL02445:Dsg4 APN 18 20446250 splice site probably benign
IGL02553:Dsg4 APN 18 20462520 missense probably benign
IGL02578:Dsg4 APN 18 20471193 missense possibly damaging 0.94
IGL02634:Dsg4 APN 18 20458580 missense probably benign 0.01
IGL02677:Dsg4 APN 18 20464876 missense possibly damaging 0.62
IGL02741:Dsg4 APN 18 20471496 missense probably benign
IGL02747:Dsg4 APN 18 20446938 missense probably damaging 0.97
IGL03342:Dsg4 APN 18 20451823 missense probably damaging 1.00
woodshed UTSW 18 20451872 nonsense probably null
R0043:Dsg4 UTSW 18 20452972 missense probably damaging 1.00
R0375:Dsg4 UTSW 18 20470879 missense probably damaging 1.00
R0537:Dsg4 UTSW 18 20458571 missense probably damaging 1.00
R0619:Dsg4 UTSW 18 20461359 missense probably benign 0.00
R0622:Dsg4 UTSW 18 20449788 missense possibly damaging 0.51
R0765:Dsg4 UTSW 18 20454646 splice site probably benign
R0786:Dsg4 UTSW 18 20449372 critical splice donor site probably null
R1114:Dsg4 UTSW 18 20466483 missense possibly damaging 0.62
R1249:Dsg4 UTSW 18 20446872 nonsense probably null
R1372:Dsg4 UTSW 18 20449676 splice site probably null
R1382:Dsg4 UTSW 18 20465124 missense probably benign 0.00
R1392:Dsg4 UTSW 18 20446247 splice site probably benign
R1442:Dsg4 UTSW 18 20462660 missense possibly damaging 0.76
R1503:Dsg4 UTSW 18 20449679 missense probably damaging 1.00
R1704:Dsg4 UTSW 18 20471589 missense probably damaging 1.00
R1716:Dsg4 UTSW 18 20462461 nonsense probably null
R1765:Dsg4 UTSW 18 20456831 missense probably benign 0.01
R1817:Dsg4 UTSW 18 20471245 missense probably damaging 1.00
R1982:Dsg4 UTSW 18 20471212 missense probably damaging 1.00
R2025:Dsg4 UTSW 18 20466636 nonsense probably null
R2097:Dsg4 UTSW 18 20471044 missense probably damaging 1.00
R2198:Dsg4 UTSW 18 20461442 missense probably benign
R3551:Dsg4 UTSW 18 20451756 missense probably damaging 1.00
R3742:Dsg4 UTSW 18 20471001 missense probably damaging 1.00
R3853:Dsg4 UTSW 18 20449234 missense probably benign
R3955:Dsg4 UTSW 18 20449375 splice site probably null
R4006:Dsg4 UTSW 18 20470965 missense probably damaging 0.97
R4012:Dsg4 UTSW 18 20451862 missense possibly damaging 0.81
R4171:Dsg4 UTSW 18 20458579 nonsense probably null
R4254:Dsg4 UTSW 18 20471538 missense probably benign 0.07
R4504:Dsg4 UTSW 18 20461436 missense probably benign 0.00
R4559:Dsg4 UTSW 18 20470921 missense probably damaging 1.00
R4607:Dsg4 UTSW 18 20471245 missense probably damaging 1.00
R4612:Dsg4 UTSW 18 20462413 missense probably benign 0.10
R4683:Dsg4 UTSW 18 20461409 missense probably benign
R4700:Dsg4 UTSW 18 20456908 missense possibly damaging 0.91
R4749:Dsg4 UTSW 18 20446831 missense possibly damaging 0.88
R4775:Dsg4 UTSW 18 20471127 missense possibly damaging 0.48
R4809:Dsg4 UTSW 18 20466621 missense possibly damaging 0.82
R5276:Dsg4 UTSW 18 20446839 missense probably benign 0.21
R5426:Dsg4 UTSW 18 20458484 missense probably damaging 1.00
R5767:Dsg4 UTSW 18 20462492 nonsense probably null
R5982:Dsg4 UTSW 18 20465169 missense possibly damaging 0.76
R6280:Dsg4 UTSW 18 20466667 missense probably damaging 1.00
R6305:Dsg4 UTSW 18 20449790 missense probably damaging 1.00
R6489:Dsg4 UTSW 18 20471363 missense possibly damaging 0.93
R7013:Dsg4 UTSW 18 20458521 missense possibly damaging 0.58
R7040:Dsg4 UTSW 18 20451852 missense probably benign 0.01
R7196:Dsg4 UTSW 18 20466480 missense probably damaging 1.00
R7432:Dsg4 UTSW 18 20446266 nonsense probably null
R7438:Dsg4 UTSW 18 20466628 missense probably damaging 0.96
R7490:Dsg4 UTSW 18 20451936 splice site probably null
R7612:Dsg4 UTSW 18 20470990 missense probably damaging 1.00
R7639:Dsg4 UTSW 18 20449712 missense probably damaging 1.00
R7905:Dsg4 UTSW 18 20454669 missense probably damaging 1.00
R8251:Dsg4 UTSW 18 20471164 missense probably damaging 1.00
R8326:Dsg4 UTSW 18 20449731 missense probably benign 0.31
R8554:Dsg4 UTSW 18 20453043 missense probably damaging 1.00
R8911:Dsg4 UTSW 18 20451872 nonsense probably null
R9059:Dsg4 UTSW 18 20471125 missense possibly damaging 0.62
R9508:Dsg4 UTSW 18 20471013 missense probably damaging 1.00
R9607:Dsg4 UTSW 18 20452990 missense probably benign 0.00
R9765:Dsg4 UTSW 18 20471277 missense probably benign 0.02
Mode of Inheritance Autosomal Recessive
Local Stock Live Mice
Last Updated 2019-09-04 9:44 PM by Anne Murray
Record Created 2016-01-08 11:36 AM by Jamie Russell
Record Posted 2016-11-16
Phenotypic Description
Figure 1. The burrito mice exhibit hair loss. A wild-type littermate is shown as reference (bottom).

The burrito phenotype was identified among G3 mice of the pedigree R4012, some of which showed hair loss on their abdomens and backs near their ears (Figure 1).

Nature of Mutation
Figure 2. Linkage mapping of the hair loss phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 79 mutations (X-axis) identified in the G1 male of pedigree R4012. Binary phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity.  Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

Whole exome HiSeq sequencing of the G1 grandsire identified 79 mutations. The hair loss phenotype was linked to a mutation in Dsg4: a T to A transversion at base pair 20,451,862 (v38) on chromosome 18, or base pair 15,688 in the GenBank genomic region NC_000084 for the Dsg4 gene. Linkage was found with a recessive model of inheritance (P = 1.257 x 10-5), wherein four affected mice were homozygous for the variant allele, and 32 unaffected mice were either heterozygous (N = 19) or homozygous (N = 13) for the reference allele (Figure 2).


The mutation corresponds to residue 766 in the NM_181564 mRNA sequence in exon 6 of 16 total exons. 



206 -A--P--M--F--M--V--N--R--Y--T--G-


The mutated nucleotide is indicated in red.  The mutation results in a valine (V) to glutamic acid (E) substitution at position 211 (V211E) in the DSG4 protein, and is predicted by PolyPhen-2 to be damaging (score = 0.814).

Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 3. Domain organization of DSG4. The burrito mutation results in a valine (V) to glutamic acid (E) substitution at position 211 (V211E). DSG4 has several domains including four cadherin repeats and two DSG repeats. Abbreviations: SP, signal peptide; PP, propeptide; EA, extracellular anchor; TM, transmembrane domain; IA, intracellular anchor; ICS, intracellular cadherin-specific sequence; LD, linker domain; TD, terminal domain.

DSG4 is a member of the desmoglein family of cadherins. Dsg4 is part of the desmosomal cadherin gene cluster on chromosome 18. The mouse genome gene cluster includes: Dsc3Dsc2—Dsc1—Dsg1β (Dsg5)—Dsg1α—Dsg1γ (Dsg6)—Dsg4—Dsg3—Dsg2 (see the record for weg) (1). Mouse and human DSG4 share 79% amino acid identity and 86% homology.


DSG4 has four N-terminal extracellular cadherin repeats, an extracellular anchoring domain (EA), a transmembrane domain, an intracellular anchoring domain (IA), an intracellular cadherin-specific sequence (ICS), a linker domain, three intracellular repeated unit domains, and a C-terminal domain (2;3).


Cadherin repeats are defined by the DRE, DXD and DXNDNXPXF motifs, and classical cadherins typically have five of these repeats in their extracellular domain, as well as a single transmembrane domain and a conserved cytoplasmic (CP) domain that interacts with α- and β-catenin and connects a cadherin molecule to the actin cytoskeleton (4).  EC repeats mediate the Ca2+-dependent dimerization of cadherin molecules and the trans-extracellular linkages between cadherin dimers of two neighboring cells. Each cadherin repeat has four calcium binding motifs that together bind three calcium ions. Calcium binding facilitates linearization and rigidification of the cadherin ectodomain, prevents ectodomain unfolding, and promotes cadherin dimerization and consequent cell-cell adhesion (5-7). The overall 3D structure of the cadherin repeat motif is quite similar to the Greek-key topology of immunoglobulin domains with seven β-strands arranged as two opposing β-sheets with N- and C-termini at the opposite ends (4;6). The overall topology of the extracellular region is that of an elongated, curved structure of tandem EC domains connected by calcium-binding linker regions (8).


The intracellular domain of the DSG proteins binds to intermediate filaments via adaptor proteins desmoplakin and plakoglobin (9). The specific functions of the IPL, DSG repeat domains, and DTD are unknown. Although the DSG repeat domain putatively regulates homodimerization (10). The function of the intracellular anchor sequence in DSG4 is unclear, but that sequence in Dsc recruits plakoglobin and desmoplakin to the membrane as well as anchors intermediate filaments (11). The ICS domain mediates interacts between the desmosomal cadherins and catenin family members (e.g., plakoglobin). The DTD putatively mediates interactions with plakophilins (9).


DSG4 has five putative calcium-binding sites (DXNDN or A/VXDXD) and five N-linked glycosylation consensus motifs (NXS/T). There are three conserved repeats: DIIVTE, NVVVTE, and NVYYAE; the function of the repeats is unknown.


The burrito mutation results in a valine (V) to glutamic acid (E) substitution at position 211 (V211E); residue 211 is within the second cadherin repeat.


DSG4 is expressed in the suprabasal epidermis as well as throughout the matrix, precortex, and inner root sheath of the hair follicle (12). Dsg4 is expressed in the anagen stage hair follicles in mouse skin (12). In vibrissae follicles, DSG4 is expressed in the cells of the matrix, precortex, and inner root sheath (12).


HOXC13, LEF1, and FOXN1 transcription factors repress Dsg4 transcription. HOXC13, LEF1, and FOXN1 are members of the Notch pathway, indicating that the Notch pathway is involved in the activation and/or maintenance of Dsg4 expression in the hair follicle (13).

Figure 4. Deficiency of DSG4 leads to impaired anchoring of the hair shaft to the hair follicle. Desmosomal cadherins, comprising multiple subtypes of desmocolins (Dsc1-3) and desmogleins (Dsg1-4), are the adhesion molecules of desmosomes, intercellular junctions that anchor the hair shaft to the hair follicle. Within desmosomes, the extracellular domains of desmocolins and desmogleins from neighboring cells form heterophilic interactions in the extracellular space, while intracellularly they are linked to plakoglobin, plakophilins, and desmoplakin.  Desmoplakin binds to keratin intermediate filaments, thereby tethering the intermediate filaments to the plasma membrane to physically strengthen the junction. Grhl1 controls the expression of Dsg1 through direct binding to the Dsg1 promoter, but not to the promoters of Dsg2, Dsg3, or Dsg4. Both Dsg1 and Grhl1 are expressed in the inner root sheath, but not in the dermal papilla cells of the hair follicle. Thus, mice deficient in Grhl1 easily lose hairs in tape-stripping tests, and these hairs are bared of the inner root sheath, companion layer, and outer root sheath tissues that remain adherent to wild type hairs removed in the same way.

The skin serves an important function as a barrier to the environment, and maintains its integrity by continuously renewing the epidermis, while also maintaining associated structures such as hair.  The surface epithelium of the skin is composed primarily of keratinocytes and is constantly regenerated as cells in the outer cornified layer are sloughed off and replaced by newly differentiated cells.  Hair is produced and maintained by the pilosebaceous unit consisting of a hair-producing follicle and a sebaceous gland composed of many different cell types. The hair follicle can be divided into 3 regions: the lower segment (bulb and suprabulb), the middle segment (isthmus), and the upper segment (infundibulum).  Eight epithelial layers are present in the hair follicle including the outer root sheath (ORS) that is continuous with the epidermis, the companion layer (CL), the inner root sheath (IRS) consisting of three layers (Henle’s, Huxley’s and cuticle) and the hair shaft, which also consists of three layers (cuticle, cortex and medulla). After hair follicles are established, hair is periodically shed and then replaced, involving periodic destruction and regeneration of hair follicles.  The hair cycle is divided into periods of follicle growth (anagen), followed by regression (catagen) and rest (telogen). During the regression phase, the lower half of the follicle undergoes apoptosis.  During the anagen phase, hair follicle growth is reinitiated as follicle stem cells are induced to proliferate.  A number of signaling pathways are implicated in skin and hair follicle morphogenesis and regeneration including Sonic hedgehog (Shh), Wnts, and TGF-β family members.


Desmosomes are multiprotein complexes that link cadherin to the intermediate filament, providing structural support for tissues that undergo mechanical stress. The desmocolins (Dsc1-3) and DSGs are the adhesion molecules of desmosomes, intercellular junctions that anchor the hair shaft to the hair follicle, and are collectively known as desmosomal cadherins. Within desmosomes, the extracellular domains of desmocolins and desmogleins from neighboring cells form heterophilic interactions in the extracellular space, while intracellularly they are linked to plakoglobin, plakophilins, and desmoplakin.  Desmoplakin binds to keratin intermediate filaments, thereby tethering the intermediate filaments to the plasma membrane to physically strengthen the junction. Dsg4 functions in an adhesive role mainly in hair follicles, while the other members of the Dsg family show variable tissue expression (e.g., Dsg2 is expressed in all tissues that have desmosomes, and Dsg1 and Dsg3 are expressed in the stratified squamous epithelia) (12).


A spontaneous mutation in Dsg4 occurs in the lanceolate hair (lah) (12;14) and lanceolate hair-J (lahJ) mouse models (15). The mutation in the lahJ mice is a single base pair insertion after nucleotide 746 within exon 7, resulting in a frameshift and insertion of three aberrant amino acids followed by a premature stop codon. The mutation in the lah mice is an A to C transversion at base pair 587. The mutation results in conversion of tyrosine 196 to a serine. The lah and lahJ mice exhibited variable hair loss, including vibrissae, but hair remained on the head and shoulders (12;15). The lahJ mice were runted, while the lah mice were not (12;14;15). With age, the skin of the mice wrinkled, and the mice developed a noninflammatory, proliferative skin disease with follicular dystrophy.  The hair fibers exhibited periodic nodules along the shaft, compaction, spiral fractures, broken tips, and lance-shaped tips. In addition to the visible phenotypes, the lah and lahJ mice also exhibit elevated levels of IgE in the serum. Mutations in rat Dsg4 lead to a similar phenotype as that observed in the mouse (16-18). Hair loss in the lah rat begins at approximately 2 weeks of age, until at 4 weeks the rats are completely bald. Hair regrowth begins after an approximate 29-day cycle of growth and loss. The epiderms of the lah rat exhibits increased proliferation (16). The skin of the Dsg4 mutant rats is thickened with a concomitant increase in basal cell proliferation; the dermis is highly collagenous (17). The hair shaft and inner root sheath exhibit irregularities, and the outer root sheath is wider than normal in some hair follicles.


Humans with mutations in DSG4 exhibit autosomal recessive hypotrichosis 6 [LAH; OMIM: #607903; (19-23)], which is characterized by hypotrichosis of the scalp, chest, arms, and legs. Hair follicles and shafts in patients with LAH are aberrant. Typical hairs in the patients with LAH are fragile and break away easily, leaving short sparse scalp hairs. LAH affects the trunk and extremities as well as the scalp, eyebrows, and eyelashes.

Putative Mechanism

The burrito mice exhibit hair loss similar to the lah mouse models, indicating loss of DSG4burrito function.

Primers PCR Primer

Sequencing Primer

PCR program

1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40x
6) 72°C 10:00
7) 4°C hold

The following sequence of 453 nucleotides is amplified (chromosome 18, + strand):

1   ctcaaggaag tcgggaaaat tcaaggaaag accagccact ctctttttat acctaatgcc
61  tggagggatt gaatctagta gaatttcaac cattctctac ctccatcctt acttatagat
121 gcactggtgg taaagttaag tgccacagat gcagatgaag acaatcactt gaattctaaa
181 attgcataca agatcatctc ccaggagcct gctggtgcac ccatgttcat ggtgaacagg
241 tacactggag aagtccgcac gatgtccaat ttccttgaca gagaggtaaa gccttctatg
301 aatgaatggt aacaatgaat ttggttttgt aaagacaaag atgagataaa ttgtgtgtga
361 ccttagtcca gtgctcagga ggaaaggaaa aatactctag tcatttttaa tgaaaattaa
421 atggtcagtg atacagattt cgttttatgc acc

Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

Science Writers Anne Murray
Illustrators Diantha La Vine, Katherine Timer
AuthorsLauren Prince, Jamie Russell, and Bruce Beutler