Hypotrichosis 11

Mendelian MONDO:0014027 Pathograph 9 Show in embeddings browser Hypotrichosis Simplex Spliceosomopathy

Hypotrichosis 11 (HYPT11) is an autosomal dominant form of hypotrichosis simplex, a nonsyndromic isolated hair loss, caused by heterozygous variants in SNRPE. SNRPE encodes SmE, one of the seven Sm proteins that form the ring-shaped core of the spliceosomal U snRNPs. In the founding report, affected members of a Spanish family, and simplex cases from the UK and Tunisia, had scanty or absent eyebrows and eyelashes and a degree of scalp and body hair loss present from birth that varied widely within the family, from slight thinning to complete loss of scalp and body hair, with skin, nails, teeth and sweating normal. The start-codon variant c.1A>G (p.Met1?) segregated in the family and arose de novo in the UK case; the Tunisian case carried the Sm-motif missense variant c.133G>A (p.Gly45Ser). In transfected cells both variants reduced the soluble, snRNP-incorporable fraction of SmE, but splicing of minigene reporters and in patient lymphocytes appeared normal. How a defect in a ubiquitous core splicing protein produces a hair-restricted phenotype is unknown.

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Mappings

MONDO
MONDO:0018914 hypotrichosis simplex Not Yet Curated
skos:broadMatch MONDO
MONDO:0018914 hypotrichosis simplex is a MONDO parent of MONDO:0014027 that spans several genes and both dominant and recessive forms, so it is broader than this entry.
👪

Inheritance

1
Autosomal dominant HP:0000006
The disease mapped as an autosomal dominant trait in a three-generation Spanish family, where the heterozygous SNRPE start-codon variant segregated with hypotrichosis. The same variant arose de novo in a UK simplex case.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family."
Linkage under an autosomal dominant model in the founding family.
PMID:23246290 SUPPORT Human clinical
"We could not identify the mutation in the healthy parents, indicating that the mutation occurred de novo in that individual"
A de novo heterozygous occurrence in a simplex case is consistent with dominant action of a single allele.
?

Discussions and Knowledge Gaps

1
Why does a heterozygous variant in SmE, a core protein of every spliceosomal U snRNP and of the U7 snRNP, affect only hair, and does it change splicing in the hair follicle?
KNOWLEDGE GAP OPEN snrpe_hair_restriction
Attached to
pathophysiology#Impaired Hair Follicle Hair Production pathophysiology#Reduced Soluble SmE for U snRNP Incorporation
SmE is expressed in all scalp cell types, yet the disease spares skin, nails, teeth and sweating. Minigene reporters and patient lymphocytes showed no major splicing abnormality, so the mis-splicing step that the spliceosomopathy module places downstream of the variant has not been observed for this disease, and the authors also raised a U7 snRNP (histone mRNA processing) contribution. A dominant Snrpe mouse mutant has no obvious hair phenotype, so no animal model exists. Other SNRPE variants cause microcephaly, which shows that different alleles reach different tissues. Transcriptome profiling of patient hair follicle cells, which the founding report proposed, has not been reported.
Show evidence (4 references)
PMID:23246290 SUPPORT In vitro / ex vivo
"When analyzing these model substrates, no major splicing abnormalities were observed"
No splicing defect was detected in the systems tested.
PMID:23246290 SUPPORT In vitro / ex vivo
"we cannot exclude the possibility that SNRPE mutations cause subtle changes in the splicing pattern of the target organ"
The authors leave a hair-follicle-specific splicing change open.
PMID:23246290 SUPPORT BACKGROUND Model organism
"these mice show no obvious skin or hair phenotype"
The dominant Snrpe mouse mutant does not model the hair phenotype.
+ 1 more reference
⚙

Pathophysiology

3
Heterozygous SNRPE Variant
A heterozygous germline SNRPE variant alters SmE, a core Sm protein of the spliceosomal U snRNPs. The start-codon variant c.1A>G and the Sm-motif missense variant p.Gly45Ser are the variants with functional data. Evidence is from human genetics (linkage, segregation, de novo occurrence).
SNRPE hgnc:11161 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SNRPE (hgnc:11161). hgnc:11161 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS
RNA binding GO:0003723 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves RNA binding (GO:0003723). GO:0003723 is a molecular function from the Gene Ontology.
small nuclear ribonucleoprotein complex GO:0030532 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves small nuclear ribonucleoprotein complex (GO:0030532). GO:0030532 is a cellular component from the Gene Ontology.
Downstream
Reduced Soluble SmE for U snRNP Incorporation
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome."
Places the causal gene product in the core of the spliceosomal U snRNPs.
PMID:23246290 SUPPORT Human clinical
"we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript."
The trigger is a heterozygous germline variant in this spliceosome component.
Reduced Soluble SmE for U snRNP Incorporation
In transfected HEK293T cells both disease variants lowered the amount of soluble SmE: c.1A>G gave full-length protein from the GTG codon at lower levels plus a mostly insoluble N-terminally truncated form, and p.Gly45Ser was incorporated into the Sm core less efficiently. The authors proposed that the variants act by reducing the soluble fraction available to U snRNPs. In lymphocytes from a c.1A>G carrier, full-length SmE was incorporated into the Sm core with near-normal efficiency, so the reduction has not been shown in patient cells. Evidence is in vitro (HEK293T overexpression, patient lymphoblastoid cells).
spliceosomal snRNP assembly GO:0000387 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spliceosomal snRNP assembly (GO:0000387). GO:0000387 is a biological process from the Gene Ontology.
Downstream
Impaired Hair Follicle Hair Production
Show evidence (3 references)
PMID:23246290 SUPPORT In vitro / ex vivo
"The two mutations identified here appear to affect the solubility of SNRPE and therefore may be pathogenic because they reduce the soluble fraction that can be incorporated into U snRNPs."
States the proposed molecular consequence of both variants.
PMID:23246290 SUPPORT In vitro / ex vivo
"However, in the case of p.Gly45Ser, the reduction in the incorporation efficiency is more substantial"
The missense variant is incorporated into U snRNPs less efficiently in transfected cells.
PMID:23246290 REFUTE In vitro / ex vivo
"only full-length protein is produced and incorporated into the Sm core with almost equal efficiency to the wild-type"
In patient lymphocytes carrying c.1A>G, Sm core incorporation was near normal, so reduced incorporation is not demonstrated in patient cells.
Impaired Hair Follicle Hair Production
Hair follicles produce too little or no hair, most consistently at the eyebrows and eyelashes, while skin, nails, teeth and sweating are spared. SmE is present in the nuclei of all hair follicle, epidermal and dermal cells of human scalp, so the restriction is not explained by expression. Whether the follicle defect is a subtle splicing change, reduced SmE dosage, or a U7 snRNP (histone mRNA 3' end processing) defect has not been tested in hair follicle cells. Evidence is human clinical phenotype plus human scalp immunohistochemistry.
hair follicle cell CL:0002559 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hair follicle cell (CL:0002559). CL:0002559 is a cell type from the Cell Ontology.
hair follicle UBERON:0002073 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hair follicle (UBERON:0002073). UBERON:0002073 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sparse or Absent Eyebrows
Sparse or Absent Eyelashes
Sparse Scalp Hair
Complete Scalp and Body Hair Loss
Absent Axillary Hair
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"we detected SNRPE immunoreactivity in the nuclei of all cells of the hair follicle, the epidermis, and the dermis"
SmE is present in hair follicle cells, the tissue that fails.
PMID:23246290 SUPPORT Human clinical
"Skin, nails, teeth, and sweating are normal in these individuals and no other abnormalities were detected."
The defect is restricted to hair among ectodermal structures.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypotrichosis 11 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Head and Neck 3
Sparse or Absent Eyebrows HP:0002223 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent eyebrow (HP:0002223). HP:0002223 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"She has sparse scalp hair and eyelashes. Eyebrows are not present."
Absent eyebrows in the UK case.
PMID:23246290 SUPPORT Human clinical
"He has almost normal scalp hair, but sparse eyebrows and eyelashes."
Sparse eyebrows in an affected cousin with near-normal scalp hair.
Sparse or Absent Eyelashes HP:0000561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent eyelashes (HP:0000561). HP:0000561 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"She shows complete alopecia of the scalp and is devoid of eyebrows and eyelashes."
Absent eyelashes in the Spanish index case.
PMID:23246290 SUPPORT Human clinical
"He has almost normal scalp hair, but sparse eyebrows and eyelashes."
Sparse eyelashes in a more mildly affected relative.
Sparse Scalp Hair HP:0002209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse scalp hair (HP:0002209), qualified as congenital onset. HP:0002209 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:23246290 SUPPORT Human clinical
"Most of the affected family members present with scanty or no eyebrows and additionally with a highly variable degree of alopecia since birth, ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
Scalp hair loss present from birth with wide intrafamilial variability.
Integument 2
Complete Scalp and Body Hair Loss Alopecia universalis HP:0002289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia universalis (HP:0002289). HP:0002289 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"Most of the affected family members present with scanty or no eyebrows and additionally with a highly variable degree of alopecia since birth, ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
The severe end of the range is complete loss of scalp and body hair.
PMID:23246290 SUPPORT Human clinical
"He shows complete alopecia of the scalp as well as absence of eyebrows and eyelashes."
Complete scalp alopecia in the Tunisian p.Gly45Ser case.
Absent Axillary Hair HP:0002221 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent axillary hair (HP:0002221). HP:0002221 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23246290 SUPPORT Human clinical
"His scalp hair is sparse. Eyelashes and eyebrows are not present."
The affected father, described in the same figure legend as lacking axillary hair, also had sparse scalp hair and no eyebrows or eyelashes.
PMID:23246290 SUPPORT Human clinical
"ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
Axillary hair is among the hair affected in the family.
🧬

Genetic Associations

1
SNRPE
Gene: SNRPE hgnc:11161 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SNRPE (hgnc:11161). hgnc:11161 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:23246290 SUPPORT Human clinical
"we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript."
Identifies the causal start-codon variant in the linked family.
PMID:23246290 SUPPORT Human clinical
"observed that the mutation segregated with the disorder"
Segregation of the variant with hypotrichosis in the family.
PMID:36814386 SUPPORT BACKGROUND Human clinical
"Heterozygous variants in SNRPE have been reported in six families with isolated hypotrichosis simplex in addition to one case of isolated non syndromic congenital microcephaly."
By 2023 heterozygous SNRPE variants had been reported in six hypotrichosis simplex families.
{ }

Source YAML

click to show 
name: Hypotrichosis 11
creation_date: "2026-10-28T05:45:00Z"
category: Mendelian
description: >-
  Hypotrichosis 11 (HYPT11) is an autosomal dominant form of hypotrichosis
  simplex, a nonsyndromic isolated hair loss, caused by heterozygous variants in
  SNRPE. SNRPE encodes SmE, one of the seven Sm proteins that form the ring-shaped
  core of the spliceosomal U snRNPs. In the founding report, affected members of a
  Spanish family, and simplex cases from the UK and Tunisia, had scanty or absent
  eyebrows and eyelashes and a degree of scalp and body hair loss present from
  birth that varied widely within the family, from slight thinning to complete
  loss of scalp and body hair, with skin, nails, teeth and sweating normal. The
  start-codon variant c.1A>G (p.Met1?) segregated in the family and arose de novo
  in the UK case; the Tunisian case carried the Sm-motif missense variant
  c.133G>A (p.Gly45Ser). In transfected cells both variants reduced the soluble,
  snRNP-incorporable fraction of SmE, but splicing of minigene reporters and in
  patient lymphocytes appeared normal. How a defect in a ubiquitous core splicing
  protein produces a hair-restricted phenotype is unknown.
disease_term:
  preferred_term: hypotrichosis 11
  term:
    id: MONDO:0014027
    label: hypotrichosis 11
synonyms:
- HYPT11
- SNRPE hypotrichosis
- hypotrichosis type 11
- SNRPE-related hypotrichosis simplex
parents:
- Hypotrichosis Simplex
- Spliceosomopathy
notes: >-
  Scope. MONDO:0014027 is the isolated hair phenotype. Two further SNRPE reports
  describe different phenotypes and are not curated under this term: a de novo
  missense variant (c.65T>C, p.Phe22Ser) in a patient with nonsyndromic primary
  microcephaly and intellectual disability (PMID:31671093), and a de novo intronic
  deletion causing exon skipping in a patient with microcephaly, congenital
  atrichia and multiple congenital anomalies, which the authors proposed naming
  SNRPE-related syndromic microcephaly and hypotrichosis (PMID:36814386). An OLS
  search of MONDO for "SNRPE microcephaly" returned no term for either. A 2021 letter reporting additional SNRPE
  variants in hypotrichosis simplex (PMID:33792916) has no abstract in PubMed and
  is not cited.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018914
      label: hypotrichosis simplex
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0018914 hypotrichosis simplex is a MONDO parent of MONDO:0014027 that
      spans several genes and both dominant and recessive forms, so it is broader
      than this entry.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The disease mapped as an autosomal dominant trait in a three-generation
    Spanish family, where the heterozygous SNRPE start-codon variant segregated
    with hypotrichosis. The same variant arose de novo in a UK simplex case.
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family."
    explanation: Linkage under an autosomal dominant model in the founding family.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We could not identify the mutation in the healthy parents, indicating that the mutation occurred de novo in that individual"
    explanation: A de novo heterozygous occurrence in a simplex case is consistent with dominant action of a single allele.
genetic:
- name: SNRPE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SNRPE
    term:
      id: hgnc:11161
      label: SNRPE
  notes: >-
    Variants in the founding report were c.1A>G (p.Met1?), which removes the
    start codon, in a Spanish family and a de novo UK case, and c.133G>A
    (p.Gly45Ser), in Sm motif 1, in a Tunisian simplex case. No ClinGen
    gene-disease validity record for SNRPE was found in
    cache/clingen/gene_validity.csv.
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript."
    explanation: Identifies the causal start-codon variant in the linked family.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "observed that the mutation segregated with the disorder"
    explanation: Segregation of the variant with hypotrichosis in the family.
  - reference: PMID:36814386
    reference_title: "Novel blended SNRPE-related spliceosomopathy phenotype characterized by microcephaly and congenital atrichia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Heterozygous variants in SNRPE have been reported in six families with isolated hypotrichosis simplex in addition to one case of isolated non syndromic congenital microcephaly."
    explanation: By 2023 heterozygous SNRPE variants had been reported in six hypotrichosis simplex families.
pathophysiology:
- name: Heterozygous SNRPE Variant
  description: >-
    A heterozygous germline SNRPE variant alters SmE, a core Sm protein of the
    spliceosomal U snRNPs. The start-codon variant c.1A>G and the Sm-motif
    missense variant p.Gly45Ser are the variants with functional data. Evidence
    is from human genetics (linkage, segregation, de novo occurrence).
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SNRPE
    term:
      id: hgnc:11161
      label: SNRPE
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  molecular_functions:
  - preferred_term: RNA binding
    term:
      id: GO:0003723
      label: RNA binding
  cellular_components:
  - preferred_term: small nuclear ribonucleoprotein complex
    term:
      id: GO:0030532
      label: small nuclear ribonucleoprotein complex
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome."
    explanation: Places the causal gene product in the core of the spliceosomal U snRNPs.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript."
    explanation: The trigger is a heterozygous germline variant in this spliceosome component.
  downstream:
  - target: Reduced Soluble SmE for U snRNP Incorporation
    causal_link_type: DIRECT
- name: Reduced Soluble SmE for U snRNP Incorporation
  description: >-
    In transfected HEK293T cells both disease variants lowered the amount of
    soluble SmE: c.1A>G gave full-length protein from the GTG codon at lower
    levels plus a mostly insoluble N-terminally truncated form, and p.Gly45Ser
    was incorporated into the Sm core less efficiently. The authors proposed
    that the variants act by reducing the soluble fraction available to U snRNPs.
    In lymphocytes from a c.1A>G carrier, full-length SmE was incorporated into
    the Sm core with near-normal efficiency, so the reduction has not been shown
    in patient cells. Evidence is in vitro (HEK293T overexpression, patient
    lymphoblastoid cells).
  role: central_effector
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: spliceosomal snRNP assembly
    term:
      id: GO:0000387
      label: spliceosomal snRNP assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two mutations identified here appear to affect the solubility of SNRPE and therefore may be pathogenic because they reduce the soluble fraction that can be incorporated into U snRNPs."
    explanation: States the proposed molecular consequence of both variants.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, in the case of p.Gly45Ser, the reduction in the incorporation efficiency is more substantial"
    explanation: The missense variant is incorporated into U snRNPs less efficiently in transfected cells.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "only full-length protein is produced and incorporated into the Sm core with almost equal efficiency to the wild-type"
    explanation: >-
      In patient lymphocytes carrying c.1A>G, Sm core incorporation was near
      normal, so reduced incorporation is not demonstrated in patient cells.
  downstream:
  - target: Impaired Hair Follicle Hair Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Hair Follicle Hair Production
  description: >-
    Hair follicles produce too little or no hair, most consistently at the
    eyebrows and eyelashes, while skin, nails, teeth and sweating are spared.
    SmE is present in the nuclei of all hair follicle, epidermal and dermal cells
    of human scalp, so the restriction is not explained by expression. Whether
    the follicle defect is a subtle splicing change, reduced SmE dosage, or a
    U7 snRNP (histone mRNA 3' end processing) defect has not been tested in
    hair follicle cells. Evidence is human clinical phenotype plus human scalp
    immunohistochemistry.
  role: effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: hair follicle cell
    term:
      id: CL:0002559
      label: hair follicle cell
  locations:
  - preferred_term: hair follicle
    term:
      id: UBERON:0002073
      label: hair follicle
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected SNRPE immunoreactivity in the nuclei of all cells of the hair follicle, the epidermis, and the dermis"
    explanation: SmE is present in hair follicle cells, the tissue that fails.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin, nails, teeth, and sweating are normal in these individuals and no other abnormalities were detected."
    explanation: The defect is restricted to hair among ectodermal structures.
  downstream:
  - target: Sparse or Absent Eyebrows
    causal_link_type: DIRECT
  - target: Sparse or Absent Eyelashes
    causal_link_type: DIRECT
  - target: Sparse Scalp Hair
    causal_link_type: DIRECT
  - target: Complete Scalp and Body Hair Loss
    causal_link_type: DIRECT
  - target: Absent Axillary Hair
    causal_link_type: DIRECT
phenotypes:
- name: Sparse or Absent Eyebrows
  category: Dermatological
  description: >-
    Scanty or absent eyebrows were present in most affected members of the
    Spanish family and in the UK and Tunisian cases.
  phenotype_term:
    preferred_term: Absent eyebrow
    term:
      id: HP:0002223
      label: Absent eyebrow
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has sparse scalp hair and eyelashes. Eyebrows are not present."
    explanation: Absent eyebrows in the UK case.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He has almost normal scalp hair, but sparse eyebrows and eyelashes."
    explanation: Sparse eyebrows in an affected cousin with near-normal scalp hair.
- name: Sparse or Absent Eyelashes
  category: Dermatological
  description: Eyelashes were sparse or absent in affected individuals.
  phenotype_term:
    preferred_term: Absent eyelashes
    term:
      id: HP:0000561
      label: Absent eyelashes
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She shows complete alopecia of the scalp and is devoid of eyebrows and eyelashes."
    explanation: Absent eyelashes in the Spanish index case.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He has almost normal scalp hair, but sparse eyebrows and eyelashes."
    explanation: Sparse eyelashes in a more mildly affected relative.
- name: Sparse Scalp Hair
  category: Dermatological
  description: >-
    Scalp hair ranged from slight thinning to sparse in many affected
    individuals, varying widely within the family.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected family members present with scanty or no eyebrows and additionally with a highly variable degree of alopecia since birth, ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
    explanation: Scalp hair loss present from birth with wide intrafamilial variability.
- name: Complete Scalp and Body Hair Loss
  category: Dermatological
  description: >-
    At the severe end, affected individuals had complete loss of scalp and body
    hair; the Spanish index case and the Tunisian case had complete scalp
    alopecia.
  phenotype_term:
    preferred_term: Alopecia universalis
    term:
      id: HP:0002289
      label: Alopecia universalis
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected family members present with scanty or no eyebrows and additionally with a highly variable degree of alopecia since birth, ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
    explanation: The severe end of the range is complete loss of scalp and body hair.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He shows complete alopecia of the scalp as well as absence of eyebrows and eyelashes."
    explanation: Complete scalp alopecia in the Tunisian p.Gly45Ser case.
- name: Absent Axillary Hair
  category: Dermatological
  description: >-
    Axillary hair was thinned or absent in some affected individuals; pubic hair
    was mainly unaffected.
  phenotype_term:
    preferred_term: Absent axillary hair
    term:
      id: HP:0002221
      label: Absent axillary hair
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His scalp hair is sparse. Eyelashes and eyebrows are not present."
    explanation: >-
      The affected father, described in the same figure legend as lacking
      axillary hair, also had sparse scalp hair and no eyebrows or eyelashes.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair"
    explanation: Axillary hair is among the hair affected in the family.
discussions:
- discussion_id: snrpe_hair_restriction
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Hair Follicle Hair Production
  - pathophysiology#Reduced Soluble SmE for U snRNP Incorporation
  prompt: >-
    Why does a heterozygous variant in SmE, a core protein of every spliceosomal
    U snRNP and of the U7 snRNP, affect only hair, and does it change splicing in
    the hair follicle?
  rationale: >-
    SmE is expressed in all scalp cell types, yet the disease spares skin, nails,
    teeth and sweating. Minigene reporters and patient lymphocytes showed no major
    splicing abnormality, so the mis-splicing step that the spliceosomopathy
    module places downstream of the variant has not been observed for this
    disease, and the authors also raised a U7 snRNP (histone mRNA processing)
    contribution. A dominant Snrpe mouse mutant has no obvious hair phenotype, so
    no animal model exists. Other SNRPE variants cause microcephaly, which shows
    that different alleles reach different tissues. Transcriptome profiling of
    patient hair follicle cells, which the founding report proposed, has not been
    reported.
  evidence:
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When analyzing these model substrates, no major splicing abnormalities were observed"
    explanation: No splicing defect was detected in the systems tested.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we cannot exclude the possibility that SNRPE mutations cause subtle changes in the splicing pattern of the target organ"
    explanation: The authors leave a hair-follicle-specific splicing change open.
  - reference: PMID:23246290
    reference_title: "Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "these mice show no obvious skin or hair phenotype"
    explanation: The dominant Snrpe mouse mutant does not model the hair phenotype.
  - reference: PMID:31671093
    reference_title: "A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identify the EMX2 mRNA, which encodes a protein required for proper brain development, as a major mis-spliced down stream target."
    explanation: >-
      A different SNRPE allele, linked to microcephaly rather than hair loss,
      produces a defined mis-splicing target, a contrast with the hair disease.