Phenotypic Mutation 'yuanxiao' (pdf version)
Alleleyuanxiao
Mutation Type missense
Chromosome14
Coordinate70,808,888 bp (GRCm39)
Base Change G ⇒ A (forward strand)
Gene Hr
Gene Name lysine demethylase and nuclear receptor corepressor
Synonym(s) rh-bmh, rh, N, bldy, ba
Chromosomal Location 70,789,652-70,810,988 bp (+) (GRCm39)
MGI Phenotype FUNCTION: This gene encodes a protein that is involved in hair growth. This protein functions as a transcriptional corepressor of multiple nuclear receptors, including thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptors, and it interacts with histone deacetylases. The translation of this protein is modulated by a regulatory ORF that exists upstream of the primary ORF. Mutations in this upstream ORF, U2HR, cause Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant form of genetic hair loss in human. [provided by RefSeq, Oct 2014]
PHENOTYPE: Mutant homozygotes exhibit hair loss, usually wrinkled skin with epidermal cysts. Females do not nurse their pups well. [provided by MGI curators]
Accession Number

NCBI Refseq: NM_021877.2; MGI:96223

MappedYes 
Amino Acid Change Arginine changed to Histidine
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000022691] [ENSMUSP00000124816] [ENSMUSP00000124042]
AlphaFold Q61645
SMART Domains Protein: ENSMUSP00000022691
Gene: ENSMUSG00000022096
AA Change: R1088H

DomainStartEndE-ValueType
Blast:JmjC 54 849 N/A BLAST
JmjC 939 1150 5.23e-38 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000022691)
SMART Domains Protein: ENSMUSP00000124816
Gene: ENSMUSG00000022096
AA Change: R1088H

DomainStartEndE-ValueType
Blast:JmjC 54 849 N/A BLAST
JmjC 939 1150 5.23e-38 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000161069)
SMART Domains Protein: ENSMUSP00000124042
Gene: ENSMUSG00000022096
AA Change: R1117H

DomainStartEndE-ValueType
low complexity region 12 21 N/A INTRINSIC
Blast:JmjC 83 878 N/A BLAST
JmjC 968 1179 5.23e-38 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000163060)
Meta Mutation Damage Score 0.6467 question?
Is this an essential gene? Non Essential (E-score: 0.000) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All mutations/alleles(31) : Chemically induced (ENU)(9) Spontaneous(17) Targeted(3) Transgenic(2)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL01805:Hr APN 14 70802737 splice site probably benign
IGL02020:Hr APN 14 70793877 missense probably benign 0.01
IGL02372:Hr APN 14 70795790 missense possibly damaging 0.94
IGL02380:Hr APN 14 70795201 missense probably damaging 0.98
IGL02554:Hr APN 14 70797306 splice site probably benign
IGL02949:Hr APN 14 70797225 missense possibly damaging 0.87
IGL03406:Hr APN 14 70800860 critical splice donor site probably null
angie UTSW 14 70805273 missense probably damaging 0.97
blofeld UTSW 14 70805525 missense probably damaging 1.00
general UTSW 14 70801124 critical splice donor site probably null
kaburo UTSW 14 unclassified
mister_clean UTSW 14 70797504 critical splice donor site probably benign
mushroom UTSW 14 70805525 missense probably damaging 1.00
prune UTSW 14 70808869 missense probably damaging 1.00
ren UTSW 14 70805525 missense probably damaging 1.00
subclinical UTSW 14 70799276 missense possibly damaging 0.89
vessel UTSW 14 70799305 nonsense probably null
R0018:Hr UTSW 14 70795717 missense probably benign
R0038:Hr UTSW 14 70805525 missense probably damaging 1.00
R0374:Hr UTSW 14 70793916 missense probably benign 0.01
R0511:Hr UTSW 14 70799352 nonsense probably null
R0609:Hr UTSW 14 70797097 missense probably benign
R1828:Hr UTSW 14 70809477 critical splice donor site probably null
R2030:Hr UTSW 14 70808888 missense probably damaging 1.00
R2266:Hr UTSW 14 70795547 missense probably benign
R2267:Hr UTSW 14 70795547 missense probably benign
R2268:Hr UTSW 14 70795547 missense probably benign
R2377:Hr UTSW 14 70795318 missense probably damaging 1.00
R3686:Hr UTSW 14 70795236 missense probably damaging 0.98
R3687:Hr UTSW 14 70795236 missense probably damaging 0.98
R3754:Hr UTSW 14 70805264 missense probably damaging 1.00
R3803:Hr UTSW 14 70795333 missense probably benign 0.01
R3846:Hr UTSW 14 70808893 missense probably damaging 1.00
R3977:Hr UTSW 14 70801024 missense probably benign 0.01
R3978:Hr UTSW 14 70801024 missense probably benign 0.01
R3979:Hr UTSW 14 70801024 missense probably benign 0.01
R4528:Hr UTSW 14 70803823 missense probably damaging 1.00
R4654:Hr UTSW 14 70801013 missense probably damaging 0.99
R4834:Hr UTSW 14 70797362 missense probably damaging 0.98
R4847:Hr UTSW 14 70793916 missense probably benign 0.04
R4863:Hr UTSW 14 70809412 missense probably damaging 1.00
R5292:Hr UTSW 14 70809432 missense probably damaging 1.00
R5452:Hr UTSW 14 70794067 missense probably damaging 1.00
R5717:Hr UTSW 14 70803616 missense probably benign 0.34
R5902:Hr UTSW 14 70795231 missense probably benign 0.02
R6000:Hr UTSW 14 70805273 missense probably damaging 0.97
R6439:Hr UTSW 14 70799276 missense possibly damaging 0.89
R6823:Hr UTSW 14 70802814 missense probably damaging 0.98
R7030:Hr UTSW 14 70801124 critical splice donor site probably null
R7213:Hr UTSW 14 70795790 missense probably damaging 0.99
R7452:Hr UTSW 14 70808926 missense probably damaging 1.00
R7468:Hr UTSW 14 70795652 missense possibly damaging 0.89
R7572:Hr UTSW 14 70799293 missense possibly damaging 0.66
R7956:Hr UTSW 14 70797327 missense probably benign
R7996:Hr UTSW 14 70801043 nonsense probably null
R7997:Hr UTSW 14 70801043 nonsense probably null
R8076:Hr UTSW 14 70795381 missense probably benign 0.00
R8101:Hr UTSW 14 70805282 missense possibly damaging 0.67
R8553:Hr UTSW 14 70804965 missense probably damaging 1.00
R8749:Hr UTSW 14 70795510 missense probably damaging 1.00
R8850:Hr UTSW 14 70799305 nonsense probably null
R8949:Hr UTSW 14 70795328 missense probably benign 0.01
R9139:Hr UTSW 14 70795079 missense possibly damaging 0.65
R9236:Hr UTSW 14 70809396 missense probably damaging 1.00
R9246:Hr UTSW 14 70808915 missense probably damaging 1.00
R9327:Hr UTSW 14 70805228 missense possibly damaging 0.91
R9337:Hr UTSW 14 70797324 missense probably benign 0.00
R9487:Hr UTSW 14 70794205 missense possibly damaging 0.77
R9487:Hr UTSW 14 70793877 missense probably benign 0.01
R9700:Hr UTSW 14 70804616 missense probably benign 0.00
X0025:Hr UTSW 14 70804391 splice site probably null
X0026:Hr UTSW 14 70805281 missense probably damaging 0.99
Mode of Inheritance Autosomal Recessive
Local Stock
MMRRC Submission 038175-MU
Last Updated 2019-09-04 9:46 PM by Diantha La Vine
Record Created 2015-03-11 11:17 AM by Zhao Zhang
Record Posted 2015-03-16
Phenotypic Description
Figure 1. Homozygous yuanxiao mice exhibit wrinkled skin and alopecia.

The yuanxiao phenotype was identified among N-nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R2030. Homozygous yuanxiao mice exhibited alopecia and wrinkled skin by postnatal day (P) 25 (Figure 1). 

Nature of Mutation

Figure 2. Linkage mapping of the alopecia phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 56 mutations (X-axis) identified in the G1 male of pedigree R2030. 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 56 mutations. The alopecia phenotype was linked to a mutation in Hr: a G to A transition at base pair 70,571,448 (v38) on chromosome 14, or base pair 17,393 in the GenBank genomic region NC_000080 encoding Hr. Linkage was found with a recessive model of inheritance (P = 7.95 x 10-4), wherein 3 affected mice were homozygous for the variant allele, and 15 unaffected mice were either heterozygous (N = 9) or homozygous for the reference allele (N = 6) (Figure 2). The mutation corresponds to residue 3,957 in the mRNA sequence NM_021877 within exon 18 of 20 total exons.

17377 TTGGATGCAGGGTTGCGCCGACGGCTAAGAGAA

1112  -L--D--A--G--L--R--R--R--L--R--E- (ENSMUSP00000124042)

1083  -L--D--A--G--L--R--R--R--L--R--E- (ENSMUSP00000022691 & NP_068677)

Genomic numbering corresponds to NC_000080. The mutated nucleotide is indicated in red.  The mutation results in an arginine (R) to histidine (H) substitution at position 1117 (R1117H) in the ENSMUSP00000124042 isoform of the Hairless (HR) protein and R1088H in the NP_068677 isoform of HR, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.00).

Illustration of Mutations in
Gene & Protein
Protein Prediction

Figure 3. HR functional domains. The N-terminal domain varies between the two isoforms of HR; only the longer isoform is shown. The position of the yuanxiao mutation is indiated in red and results in an arginine to histidine substitution at residue 1117 of the HR protein encoded by the ENSMUST00000163060 cDNA transcript, or at position 1088 in the isoform encoded by the ENSMUST00000022691 cDNA transcript (not shown). NMTS, nuclear matrix targeting signal; RD, repression domain; NLS, nuclear localization signal; ID, interacting domain; ZF, zinc finger domain; ROR, retinoic acid receptor related orphan receptor; TR, thyroid hormone receptor. Click on the image to view other mutations found in HR. Click on each mutation for more specific information.

The mouse HR protein contains 1211 amino acids (a shorter 1182 amino acid isoform differs only at the N-terminus) (Figure 3). The HR protein contains a potential DNA-binding zinc finger domain consisting of a highly conserved six cysteine motif located within a loop region at amino acids 585-620 (for mouse HR). A novel bipartite nuclear localization signal (NLS) was identified at amino acids 409-427 consisting of the sequence KRA(X13)PKR (1). A novel nuclear matrix targeting signal (NMTS) at amino acids 111-156 is also necessary for its nuclear sub-localization (2). Repressive domains (RD) are located at amino acids 210-423 (RD1), 725-839 (RD2), and 839-956 (RD3). The RD2 domain contains regions that interact with the thyroid hormone receptor (TR), the retinoic acid receptor related orphan receptor α (RORα) and the vitamin D receptor (VDR) (3-5).  Domains that have been shown to interact with TR are located at amino acids 792-805 (TR-ID1 for TR interacting domain 1) and amino acids 1001-1013 (TR-ID2) (3). RORα-interacting domains (ROR-ID) are located at amino acids 561-565 and 753-757 (4). HR contains two LXXLL motifs known as nuclear receptor (NR) boxes that are present in nuclear receptor coactivators, and are known to interact with the α-helical AF-2 motif present in the ligand binding domain (LBD) of nuclear receptors (1;6). The HR protein also contains a JmjC domain at amino acids 968-1179. The yuanxiao mutation results in the substitution of an arginine with an histidine at amino acid 1117 in the JmjC domain.

Please see the record for prune for more information about hairless.

Putative Mechanism

HR is a nuclear receptor corepressor that is thought to regulate hair cell cycling by interacting with and repressing nuclear hormone receptors to control gene expression. Mutations and deletions at the C-terminus of human HR can cause Alopecia Universalis Congenita [(7); OMIM: #203655], atrichia with popular lesions [(8-10); OMIM: #209500], and/or hypotrichosis 4 (OMIM: #146550). Patients with these conditions are normally born with hair that subsequently falls out resulting in a complete or nearly complete absence of all hair. In the mouse, the classical hairless (hr) and rhino (hrrh) homozygous mutants with mutations in the hr gene develop a normal first coat, but do not reinitiate subsequent hair cycles resulting in alopecia (11-13). Histologically, the skin of hairless and rhino mice are normal until the first hair cycle is nearly complete. Just before the normal loss of the first coat, the hair follicles of these mutants appear altered. As the mutant animals age there is hypertrophy of the sebaceous glands, loss of adipose tissue, and the development of various types of cysts from the hyperkeratotic upper part of the hair canals, and the sheaths of the abnormal follicles stranded in the dermis (13-15). Toward the end of HF morphogenesis, the proximal hair bulb undergoes premature and massive apoptosis associated with a lack of coordination of cell proliferation in defined HF compartments (14). Although the hair follicle defects in both hairless and rhino mutants are similar, animals homozygous for rhino alleles also develop thickened and severely wrinkled skin (12). The yuanxiao phenotype mirrored other phenotypes attributed to mutations in Hr (see prune, Kaburo, and mister_clean as well as alleles listed at MGI), indicating loss of HR function.

Primers PCR Primer
yuanxiao_pcr_F: GCTTCAGCACCCTATTGAACC
yuanxiao_pcr_R: AAGACTTCAAGACCCTTGGC

Sequencing Primer
yuanxiao_seq_F: TTGAACCTGATCTTCCAAAGAGTCC
yuanxiao_seq_R: CTGCCTAGCTTTCTATCAGGTAGAG
Genotyping

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 417 nucleotides is amplified (chromosome 14, + strand):


1   gcttcagcac cctattgaac ctgatcttcc aaagagtcca ctccccttcc tctctgaatg
61  cttgccttca tccccactga cattcatctt cctttctctt cttgaaggtg tgcccagctg
121 gagcaggaac cttggagcct ggtgccccag gcagctgcta cttggatgca gggttgcgcc
181 gacggctaag agaagagtgg ggtgtgagct gctggaccct gctgcaggct cctggggaag
241 cggtgctggt cccggctggg gcgccccatc aggtgcttac ctggtgggtg ggggttaaca
301 aaagatcaga gtatcagaag tagcaaggag tcctgatcat acagcattct ctacctgata
361 gaaagctagg cagggcagga agccatggag atagaaagcc aagggtcttg aagtctt


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

References
Science Writers Anne Murray
Illustrators Peter Jurek
AuthorsZhao Zhang, Doan Dao, Hexin Shi, Lei Sun, Jianhui Wang, Ying Wang, Bruce Beutler