Table 1.
Missense mutations and the resultant phenotypes observed in the families described in the present study.
Figure 1.
(A–D) Each of the four families segregated hereditary hypotrichosis and showed linkage to the LPAR6 gene. Circles and squares represent females and males, respectively. Clear symbols represent unaffected individuals while filled symbols represent affected individuals. Double lines are indicative of consanguineous unions. (E–G) Affected members III-2 and IV-6 (family A) and IV-13 (family C) showed woolly scalp hair/sparse scalp hair, sparse eyebrows and eyelashes.
Figure 2.
Characterization of LPAR6 specific mutations at structure level.
(A) 3D representation of LPAR6structure in ribbon form. Individual α-helices are indicated by distinct colors: α1, magenta; α2, green; α3, cornflower blue; α4, brown; α5, pink; α6, orange red and α7, olive. β-sheets are indicated by yellow color. (B) Schematic representation of LPAR6 secondary structures indicating the directionality of β-sheets to the extracellular part, while narrow end of α-helices points to the cytosol, making a groove-like structure. Corresponding positions of known amino acids undergoing substitutions are indicated which show that I188, N248 and L277 lie to the extracellular part of α-helices, while D63 and G146 residues are near the cytosolic part. Surface view of groove-like structure is shown to visualize the residual positions. (C) Hydropathy plot analysis of normal and mutated LPAR6 amino acids performed by MPEx tool. (D) Membrane spanning profile studies of individual α-helices for LPAR6WT, LPAR6D63V and LPAR6N248Y.
Figure 3.
Residual contributions explored through molecular dockings of LPAR6WT and LPA binding.
Labels are indicated by black color. Individual α-helices are indicated by distinct colors: α1, magenta; α2, green; α3, cornflower blue; α4, brown; α5, pink; α6, orange red and α7, olive. Loop regions and β-sheets are indicated by gold color.
Table 2.
Hydropathy analysis results for LPAR6WT, LPAR6D63V and LPAR6N248Y proteins.
Figure 4.
Comparative analysis of conformational changes in LPA-bound LPAR6 structures at residual level.
Individual mutations are indicated by distinct colors. Binding residues are labeled in black color.
Table 3.
Comparative binding analysis of LPAR6WT and LPAR6MT structures bound to LPA. Similar residues in multiple complexes are indicated in bold.
Figure 5.
Overview of LPAR6-LPA dependent pathways involved in hair follicle development.
Three possible pathways (β-Catenin, Rho and EGFR) are known to occur in the inner root of hair sheath. A dotted line arrow indicates TGF-α inter-linkage with EGFR pathway. The β-catenin together with Cadherins may activate HK genes and help in hair development [34]. Rho and EGFR pathways are linked with each other by functional activity of TGF-α which is directly involved in the activation of EGFR. Rho signaling cascade (GTP binding proteins) and EGFR proteins activate MEK/ERK which results in the development of hair follicle by regulating the downstream transcriptional activity [35], [36]. HK, hair keratins; G-Protein αβδ, GTP binding proteins; Gα-12/13, Subunit of GTP binding protein alpha; RhoA, Ras homolog gene family member A; ROCK, Rho associated protein kinase; PKC, Protein kinase C; Pro TGF, Protein transforming growth factor; EGFR, Epidermal growth factor receptor; SOS protein, son of seveless protein; GPR1, G-protein couple receptor 1; MEK, MAPK/ERK kinases; ERK, extracellular signal regulated kinases.