EDAR – Autosomal Recessive Hypohidrotic Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia (MONDO:0016535) is a developmental disorder characterized by sparse hair, hypodontia and reduced sweat gland function. While the X-linked form is caused by mutations in EDA, autosomal recessive cases arise from biallelic variants in the ectodysplasin A receptor gene (EDAR). Clinical hallmarks include hypotrichosis, hypohidrosis (HP:0000966), and dental agenesis (HP:0000668). Autosomal recessive inheritance has been confirmed in multiple consanguineous pedigrees and sporadic cases.

Genetic evidence stems from compound heterozygous and homozygous mutations across at least 11 affected individuals in consanguineous families (PMID:16029325) with segregation of pathogenic EDAR alleles in both maternal and paternal lineages. Case reports describe novel splice site changes (c.51+1G>A), missense substitutions (c.1124G>A (p.Arg375His)), and small deletions (c.84delC (p.Ser29fsTer74)) in Japanese, Spanish, Pakistani and Middle Eastern patients, illustrating genetic heterogeneity and recurrence of loss-of-function alleles (PMID:15373768; PMID:16029325).

The variant spectrum includes at least 45 distinct mutations: 24 missense changes within the death and TNFR domains, 10 splice-site variants leading to exon skipping, 7 frameshifts or nonsense alleles, and copy-number duplications with dominant-negative effects. A recurrent missense variant p.Gly382Ser has been reported in multiple Pakistani families, suggesting a population-specific founder effect. Representative pathogenic change: c.1124G>A (p.Arg375His).

Functional assays demonstrate that death-domain substitutions abolish EDAR–EDARADD interaction and reduce NF-κB activation. The p.Arg375His mutant fails to recruit EDARADD and shows <10% reporter activity compared to wild type in HEK293 cells, confirming loss-of-function (PMID:15373768). Co-immunoprecipitation and luciferase assays of EDARADD-binding mutants (e.g., p.Leu112Arg) reveal dominant-negative effects in autosomal dominant pedigrees, but recessive alleles uniformly impair NF-κB signaling (PMID:17354266).

No significant conflicting evidence has emerged to refute EDAR’s role in recessive HED. Autosomal dominant variants, while clinically overlapping, involve heterozygous missense or truncating alleles in the last exon and may act via dominant-negative mechanisms.

In summary, biallelic loss-of-function mutations in EDAR cause autosomal recessive hypohidrotic ectodermal dysplasia with high clinical penetrance. Genetic testing of EDAR in HED patients enables precise recurrence risk estimation and informs management of ectodermal defects.

References

• The Journal of Investigative Dermatology • 2004 • A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene. PMID:15373768
• The British Journal of Dermatology • 2005 • Novel mutations in the EDAR gene in two Pakistani consanguineous families with autosomal recessive hypohidrotic ectodermal dysplasia. PMID:16029325
• European Journal of Human Genetics • 2008 • Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. PMID:18231121
• Human Mutation • 2007 • Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus. PMID:17354266
• Dermatology (Basel) • 2011 • A missense mutation in the death domain of EDAR abolishes the interaction with EDARADD and underlies hypohidrotic ectodermal dysplasia. PMID:21876339

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