Allele | flake | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Mutation Type | missense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Chromosome | 19 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Coordinate | 44,388,769 bp (GRCm39) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Base Change | G ⇒ T (forward strand) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Gene | Scd1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Gene Name | stearoyl-Coenzyme A desaturase 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Synonym(s) | SCD, stearoyl-CoA desaturase, Scd-1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Chromosomal Location | 44,382,889-44,396,148 bp (-) (GRCm39) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an enzyme involved in fatty acid biosynthesis, primarily the synthesis of oleic acid. The protein belongs to the fatty acid desaturase family and is an integral membrane protein located in the endoplasmic reticulum. Transcripts of approximately 3.9 and 5.2 kb, differing only by alternative polyadenlyation signals, have been detected. A gene encoding a similar enzyme is located on chromosome 4 and a pseudogene of this gene is located on chromosome 17. [provided by RefSeq, Sep 2015] PHENOTYPE: Homozygotes for targeted and spontaneous mutations exhibit alopecia, scaly skin, sebaceous gland hypoplasia, impaired ocular lubrication and synthesis and storage of triglycerides, higher lipid oxidation, reduced growth, and lower fertility in females. [provided by MGI curators] |
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Accession Number | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mapped | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Amino Acid Change | Threonine changed to Lysine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Institutional Source | Beutler Lab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Gene Model | not available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
AlphaFold | P13516 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SMART Domains |
Protein: ENSMUSP00000036936 Gene: ENSMUSG00000037071 AA Change: T227K
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Predicted Effect | probably damaging
PolyPhen 2 Score 0.998 (Sensitivity: 0.27; Specificity: 0.99) |
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Meta Mutation Damage Score | Not available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Is this an essential gene? | Probably essential (E-score: 0.949) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Phenotypic Category | Autosomal Recessive | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Candidate Explorer Status | loading ... | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Single pedigree Linkage Analysis Data |
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Penetrance | 100% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Alleles Listed at MGI | All alleles(13) : Targeted, knock-out(1) Targeted, other(1) Gene trapped(6) Spontaneous(4) Chemically induced(1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Lab Alleles |
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Mode of Inheritance | Autosomal Recessive | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Local Stock | Embryos, gDNA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MMRRC Submission | 010467-UCD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Last Updated | 2016-05-13 3:09 PM by Stephen Lyon | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Record Created | unknown | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Record Posted | 2007-07-11 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Phenotypic Description |
The flake phenotype was identified as a visible phenotype among G3 mice mutagenized with ENU (1). At weaning age, flake mice develop alopecia and chronic exfoliative dermatitis that progress with age (Figure 1). Disruption of epidermal integrity is observed in flake mice. Flake hairs are short and rough. Mutants have small eyes with excessive excretion.
The cholesterol ester content of flake skin lipid extracts is reduced compared to wild type, and flake sebaceous glands atrophy abnormally.
Flake mice displayed increased susceptibility to subcutaneous infection with gram-positive (Streptococcus pyogenes and Staphylococcus aureus), but not gram-negative (E. coli) bacteria. When wild type mice were clear of cutaneous bacteria at 8 days post-infection with S. pyogenes, flake skin still contained bacteria at levels near the amount of the initial inoculum. Flake mice had normal resistance to gram-positive bacteria when introduced intravenously or intratracheally. Intradermal injection of palmitoleate every other day for 9 days after infection with S. aureus resulted in a 90% reduction in cutaneous S. aureus in wild type mice, but in flake mice, bacterial growth was only reduced during days 1 to 4 post-infection, and S. aureus was still present in flake skin 2 weeks after inoculation. However, such intradermal palmitoleate injections significantly reduced lesion size in flake mice, similar to that observed in wild type mice..
Scd1 transcription is upregulated in response to S. aureus infection in wild type, but not in Tlr2-/- mice, indicating that this upregulation is TLR2-dependent. Treatment of peritoneal macrophages with MALP-2, a TLR-2 agonist, increased in Scd1 expression. MALP-2, but not LPS (a TLR4 agonist) treatment of the human sebocyte cell line, SZ95, induced IL-6 and IL-8 production.
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Nature of Mutation |
The flake mutation was mapped to Chromosome 19, and corresponds to a C to A transversion at position 938 of the Scd1 transcript, in exon 5 of 6 total exons.
922 TGCTTCATCCTGCCCACGCTGGTGCCCTGGTAC
222 -C--F--I--L--P--T--L--V--P--W--Y-
The mutated nucleotide is indicated in red lettering, and results in a conversion of threonine to lysine at residue 227 of the SCD1 protein.
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Illustration of Mutations in Gene & Protein |
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Protein Prediction |
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Expression/Localization |
SCD1 is expressed in liver, adipose tissue, eyelid, and in undifferentiated sebocytes of the skin (2). SCD1 is anchored in the endoplasmic reticulum.
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Background |
Three spontaneous mutant alleles of Scd1, designated asebia, asebia-J and asebia-2j (hereafter referenced collectively as “asebia”), exist in mice, and homozygosity for any of these alleles results in alopecia, atrophic sebaceous glands, and scaly skin, as well as narrow eye fissures (6;7). A targeted SCD1-null mouse also displays the same phenotypes (8). Histological analysis of Scd1 mutant mice revealed a thickened epidermis with large intracellular spaces, and abnormal sebaceous cell differentiation (7;8). Fewer lipid droplets and distorted smooth endoplasmic reticula were observed in Scd1 mutant skin. Lipid analysis of extracts from asebia and Scd1-/- skin or eyelids revealed reduced levels of triglycerides, cholesterol esters and wax esters compared to wild type (7;8).
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Putative Mechanism |
Together with the epidermis and hair follicles, sebaceous glands form part of the body’s skin, which provides a protective barrier against microbes while keeping in essential body fluids. Sebaceous glands are an appendage of the hair follicle, and generate sebocytes, which produce lipids and sebum. These sebocytes release lubricating lipid complexes containing wax esters, triglycerides and cholesterol esters when they disintegrate, providing protection against bacterial infections and preventing moisture evaporation.
Several proteins are known to control sebocyte homeostasis and function [reviewed in (15)], but little is known about how SCD1 interfaces with these molecules in sebocytes. However, one link may be through peroxisome proliferator-activated receptor (PPAR)-γ. A recent report demonstrated that PPAR-γ positively regulates SCD1 expression in vascular endothelial cells during shear stress (16). PPAR-γ is believed to contribute to sebocyte differentiation and lipid production as an adipogenic transcription factor expressed in differentiating sebocytes (17). PPAR-γ-null embryonic stem cells contribute poorly to sebaceous gland development in mice (18). Thus, PPAR-γ may signal through SCD1 to maintain sebocyte homeostasis. This is further supported by a study demonstrating that SCD1 deficiency attenuates fasting-induced liver steatosis in PPAR-α-deficient mice (19).
No other studies document a role for SCD1 in the innate immune response. However, given the role of SCD1 in maintaining sebaceous glands and overall skin integrity, it is not surprising that SCD1 is involved in the skin’s defense against microbes. In support of this, palmitoleic acid has been shown to inhibit the growth of gram-positive bacteria in culture (20). Dermal infiltrates from asebia mice were shown to be rich in mast cells and macrophages (21). During infection and wound response, epidermal cells regulate cell polarity, movement and adhesion via the RhoGTPases, p120-catenin and α-catenin, which affect the transcriptional status of NF-κB, and in turn cytokine production (22;23). The Scd1 promoter region contains several NF-κB binding sites (1), suggesting that the TLR2-dependent innate response involves regulation of lipid composition through transcriptional control of Scd1.
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Primers | Primers cannot be located by automatic search. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Genotyping |
Flake genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Primers for PCR amplification
Flake(F): 5’-CCGAGAGACTAAGGGATTCTTATGGTTCCGTG -3’
Flake(R): 5’- GGACTCAGAGGCTCATTATAGGCAGCATTTAGAC -3’
PCR program
1) 94°C 2:00
2) 94°C 0:15
3) 60°C 0:20
4) 68°C 4:00
5) repeat steps (2-4) 35X
6) 68°C 5:00
7) 4°C ∞
Primers for sequencing
Flake_seq(F): 5’- ACAGTTCGTGTAGGTTTGAGAGTCCTCTATC -3’
Flake_seq(R): 5’- CCTCCTGGTTCCTCTGGTTCCTAAACAAAC -3’
The following sequence of 3566 nucleotides (from Genbank genomic region NC_000085 for linear DNA sequence of Scd1) is amplified:
4113 ccgagaga ctaagggatt cttatggttc
4141 cgtgaaaaac agaccctcac cccaaaacca aagaacactg gcatcaggga aggcgccttg
4201 gcaacttcca ctactgaaat ttgcctgttg gtgagtctcc cactgtcttg tcttgcaggg
4261 attttctact acatgaccag cgctctgggc atcacagccg gggctcatcg cctctggagc
4321 cacagaactt acaaggcacg gctgcccctg cggatcttcc ttatcattgc caacaccatg
4381 gcgttccagg taagaagcga gtgctgtggc tgtgtctcca tccccaggat gatctgagtg
4441 agccgtgggg gatcagcatc tagggaggaa ttataaggac caccactgac tgcctttttt
4501 tggtgtcctg gactcatctc aagtaaaaca ggttcaggac cgatatcgta tctcacagtg
561 tgtttgccta aagggccctg ctgcaggatc catgcactga ccctgggttc ctgagctctt
4621 actggagagt caactcatac tttcctgtga ccatcatgga atgtcaccac aatgggacta
4681 acagtgatat gtcacgtaat tgggaattct attggctgtg ctgggcactt gtcataagtt
4741 aacacattaa gtcctcatag acatattggt gggtattatc attatcacac ttatttttat
4801 tctctgacat aagatctcac tgagtagcca tggctggcct ggaactcact atgtagatca
4861 ggctggcctc tgccttcaca gtactgggat taaaggtgcg ctttagtcgg gcgtggtggc
4921 gcatgccttt aatcccagca cttgggatta aagtgagttc caggacagcc agggctacac
4981 agagaaaccc tgttacccac cacttaactg actctgaaag gttggcctgg tgacccatgt
5041 tcttgcagag actgctgggt tagctaggtc aggtatgaaa gttgacttat agttaaatga
5101 ggagagttgg gggaattttt agttgttggg cactggatga ctttcgaagg ctttctcttc
5161 atacaagaga aaaatcagga tccaaattat tcccatttat tgacaatatg tcaaaagagt
5221 ttcccgtatg ccccggagga gctcagaggt cccatggaaa tgggctcatg ctcattaatt
5281 acgtgctggc ttaaaattag gttgggtggg ctgtcacctg tgaaagcatc tgggtgggac
5341 tccctgcatc tttccccgga ctccctgggg tccacctgcc ttaggatctc tgcccccagg
5401 ttcccacatt cctttcttca agaactgcag cgttctttgt gagagctgtg actttcctcc
5461 ccgcctcctc acacacaacc ttcagtgtgc tctgagactt tgccaaataa gctccaggga
5521 caaaggtaca aaagagcagc ccccaaggtc tcctttggag ctacagccct aggggcttag
5581 agttctctta ggcactggat tacctcagga gagcctctct tctcaatact gggttcctct
5641 ttcctgtgct tccagaatga cgtgtacgaa tgggcccgag atcaccgcgc ccaccacaag
5701 ttctcagaaa cacacgccga ccctcacaat tcccgccgtg gcttcttctt ctctcacgtg
5761 ggttggctgc ttgtgcgcaa acacccggct gtcaaagaga agggcggaaa actggacatg
5821 tctgacctga aagccgagaa gctggtgatg ttccagagga ggtaagggat ggggtggggg
5881 tggaacccag ggcacctggg gtttagggat tccacatttt ctcttaggat gtataaaata
5941 ataattaagg tgatttactg gatcgataag cttgaaatca ctaaagtctc caattcaaca
6001 tcccataggt tcccaaggca taatgtttct gcctgagcca tcctgctaaa accaataact
6061 ataacattgg tcctagtctg gtactcatgg ctgagcggtt taccttcaag gaattttcag
6121 ggtatttggg gttgaaggaa tgagccttaa ttagctccac ataaagcagg atggtgcctg
6181 cttaccatga ttaaggagga ggagatacag ctcggtggat gcacaatgta actagtgcag
6241 tagcgtcagg atccaaccaa cacagaggct ctggcagtgt ggtgggcagg gactgcaatg
6301 gaatgtcaag acatgctcct ttctggcata gtccttctct gtgagatgta ccgtgtgaca
6361 ggagccaggc tgccaggaca gacagagtca gtattgattc agtcagtttc aggggactaa
6421 ctcaagcaaa cattctctgg cagccgtggg acacggcttt caagataggt gaaagtagtg
6481 atggagctag ggagataaca gccagagtca caggttagac cagcaggagg cttcagctag
6541 ggaagtagtg agcagatgga caggaacgac gccaagggag tctcagtgat acaactgctg
6601 agggatgtcc tcggcctggt ttatagggat tgaagaatgg gacagggctg ctagagtgac
6661 agaaacctgc agaagatcaa ggacatttga tgtgtcttct gggcgggggt ggggggtggg
6721 gggtgagcag aacagagacc cacagggtga tgggaagtga aggcatgaca cttgccttac
6781 tctgccaaaa acctcaacgg gcaagaagga gctcaaaggc tgatggagaa cagcccagga
6841 agcagaattg gcaagtgagg ttgtgatttg attcccaact ggtttgacga gcaggacctt
6901 atgttcctat gaaaaaaagt aatggctttg tagtcaggaa tagaagtgac aggagacaaa
6961 ctatacccag tgggatccta gaagaatatt ggcacatttg tgtatcccat ccaaagaaag
7021 agaacaccat gcttaagatt ttgttatcac ctttcctctg gctgatagtc tgtcccatcc
7081 cttgacgtaa aaatgataca acgctgccta attagggggg gacagttcgt gtaggtttga
7141 gagtcctcta tccagactct gtgtgatctc tccatgtagg tactacaagc ccggcctcct
7201 gctgatgtgc ttcatcctgc ccacgctggt gccctggtac tgctggggcg agacttttgt
7261 aaacagcctg ttcgttagca ccttcttgcg atacactctg gtgctcaacg ccacctggct
7321 ggtgaacagt gccgcgcatc tctatggata tcgcccctac gacaagaaca ttcaatcccg
7381 ggagaatatc ctggtttccc tgggtgccgt gggtaagtca ctagtccccg acaggaccgt
7441 atctaggggc cttccggttg tgttgtttgt ttaggaacca gaggaaccag gaggacctgt
7501 tttgtgagtt ctgtgtagtt cggtttttcc accataaaac tgggggttgg ggagagtata
7561 ttggaggcct tacgagtgtc tggtaagcaa cagctcttaa tgtaaaaagg aaaggggaag
7621 aaggcttata ggttgtaaaa caatgtctaa atgctgccta taatgagcct ctgagtcc
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated C is shown in red text.
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References | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Science Writers | Eva Marie Y. Moresco | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Illustrators | Diantha La Vine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Authors | Philippe Georgel, Karine Crozat, Bruce Beutler |