LPAR6 – Isolated Familial Woolly Hair Disorder

Autosomal recessive variants in LPAR6 underlie isolated familial woolly hair disorder (MONDO:0008686), characterized by tightly curled scalp hair with variable hypotrichosis. Across at least seven unrelated families, biallelic loss-of-function and missense mutations have been reported in more than 16 probands, consistent with autosomal recessive inheritance and confirmed segregation in consanguineous pedigrees and compound-heterozygous cases.

Genetic analyses have identified a spectrum of pathogenic alleles in LPAR6, including nonsense (c.756T>A (p.Tyr252Ter)) and frameshift variants disrupting receptor expression, as well as missense substitutions that impair lysophosphatidic acid (LPA) binding. The recurrent c.188A>T (p.Asp63Val) founder allele has been observed in multiple Pakistani kindreds, while private missense changes such as c.587C>T (p.Pro196Leu) and c.562A>T (p.Ile188Phe) have been documented in Turkish and other families, respectively ([PMID:25828854]; [PMID:21070332]; [PMID:25119526]; [PMID:28425126]; [PMID:31077348]; [PMID:18297070]).

Functional assays have consistently demonstrated loss of LPA6 receptor activity: expression studies in patient hair follicles show absent transcript from alleles with promoter insertions and truncated proteins, and in vitro signaling assays reveal abolished LPA-mediated responses for p.Tyr252Ter; molecular modeling of missense mutants corroborates altered ligand orientation and loss of receptor function.

No conflicting reports have been published to date, and concordant genetic and experimental data robustly support LPAR6 haploinsufficiency and receptor loss-of-function as the pathogenic mechanism in woolly hair disorder. Comprehensive sequencing of LPAR6 is therefore clinically indicated for diagnostic confirmation in individuals with autosomal recessive woolly hair and hypotrichosis.

Key take-home: Biallelic pathogenic LPAR6 variants cause autosomal recessive woolly hair disorder via receptor loss-of-function, supporting targeted genetic testing and future therapeutic development.

References

• Journal of dermatological science • 2015 • Analysis of unique mutations in the LPAR6 gene identified in a Japanese family with autosomal recessive woolly hair/hypotrichosis: Establishment of a useful assay system for LPA6. PMID:25828854
• 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
• Congenital anomalies • 2018 • Novel sequence variants in the LIPH and LPAR6 genes underlies autosomal recessive woolly hair/hypotrichosis in consanguineous families. PMID:28425126
• International journal of dermatology • 2019 • Biallelic mutations in the LPAR6 gene causing autosomal recessive wooly hair/hypotrichosis phenotype in five Pakistani families. PMID:31077348
• Nature genetics • 2008 • G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. PMID:18297070

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