LPAR6 – Hypotrichosis 8

LPAR6 encodes the lysophosphatidic acid receptor 6, a G protein–coupled receptor essential for hair follicle development and hair growth. Biallelic loss-of-function variants in LPAR6 underlie autosomal recessive hypotrichosis 8 (MONDO:0010206), characterised by sparse scalp hair without other systemic abnormalities.

Genetic Evidence: Autosomal recessive inheritance is supported by a homozygous missense variant c.188A>T (p.Asp63Val) identified in a Pakistani family with hypotrichosis 8 in the elder brother, segregating in the expected recessive pattern and absent in unaffected sibs ([PMID:27472364]). This variant was previously reported in five additional consanguineous families from Pakistan, totaling six probands carrying homozygous p.Asp63Val ([PMID:27472364]).

Variant Spectrum: To date, pathogenic LPAR6 alleles include recurrent missense substitutions (p.Asp63Val, p.Ile188Phe, p.Gly146Arg, p.Lys16Met), truncating mutations (p.Gln155Ter, p.Lys125fs, p.Tyr252Ter), and frameshifts, indicating that both missense and null alleles disrupt P2Y5 receptor function.

Functional Evidence: In vitro assays demonstrate that p.Asp63Val and other receptor missense mutants show altered ligand binding orientations and impaired downstream signalling upon LPA stimulation ([PMID:25119526]). A Turkish family–derived p.Pro196Leu variant similarly disrupts P2Y5 signalling in cell‐based reporter assays ([PMID:21070332]). These concordant functional studies confirm a loss-of-function mechanism.

Conflicting Evidence: No reports to date dispute the role of LPAR6 in autosomal recessive hypotrichosis.

Conclusion: Multiple independently ascertained probands with biallelic LPAR6 variants, segregation data, and consistent in vitro loss-of-function assays provide strong evidence for LPAR6 involvement in hypotrichosis 8. Genetic testing for LPAR6 variants informs diagnosis and enables accurate genetic counseling for families affected by autosomal recessive hypotrichosis.

References

• Genes • 2016 • Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan. PMID:27472364
• Clinical and experimental dermatology • 2011 • A novel mutation in LPAR6 causes autosomal recessive hypotrichosis of the scalp. PMID:21070332
• PloS one • 2014 • In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis. PMID:25119526

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