In this study, we analyzed two Guyanese families with ARWH and identified mutations in the LIPH
gene in both families. Affected individuals in Family A carry compound heterozygous mutations Ex7_8del and 1303_1309dupGAAAACG in the LIPH
gene, which were inherited on their paternal and maternal alleles, respectively (). These are the first compound heterozygous mutations identified in the LIPH
gene. Secondly, affected individuals in Family B are homozygous for the mutation 659_660delTA in the LIPH
gene. All three mutations result in a frameshift and downstream PTC. Most likely, aberrant transcripts from both the Ex7_8del and 659_660delTA alleles would be largely degraded due to nonsense-mediated mRNA decay (Maquat, 1996
; Frischmeyer and Dietz, 1999
), leading to loss of expression of LIPH protein. By contrast, because the mutation 1303_1309dupGAAAACG exists in the last exon of the LIPH
gene, the mutant allele with this mutation is likely to generate a truncated LIPH protein which would lack only 15 amino acid residues in its C-terminus as compared with the wild type LIPH protein (). Nevertheless, the aberrant protein would not possess a cysteine residue at amino acid 446 which is considered to be important for the formation of a disulfide bond () (Jin et al., 2002
), and thus is predicted to severely affect the structure of LIPH protein.
The mutations Ex7_8del and 659-660delTA were previously identified in several Pakistani families with ARWH (Jelani et al., 2008
; Shimomura et al.
, 2008c). Haplotype analysis suggests a common founder for these mutations between the Pakistani and Guyanese families, living in geographically distinct regions (). Interestingly, history reveals that more than 200,000 people emmigrated from India to Guyana between 1838 and 1917 (Bisnauth, 2000
), and since Pakistan was separated from India in the 1940s, it is plausible that India is the common source for these chromosomes. Indeed, it is noteworthy that both families emigrated from India to Guyana about 100 years ago, and all members of the extended pedigrees of both families are of Indian descent.
Mutations in the LIPH
gene were originally reported to underlie an autosomal recessive form of hypotrichosis (Kazantseva et al., 2006
; Ali et al., 2007
). Recently, we identified several pathogenic mutations in Pakistani families affected with ARWH (Shimomura et al.
, 2008c). During early childhood, all affected individuals in our families showed mainly WH, but then exhibited wide variability in the hypotrichosis phenotype with aging. While some affected individuals continued to show only WH, others suffered hair loss, leading not only to WH, but also hypotrichosis. In the most severe cases, the hypotrichosis became the only phenotype, leading even to complete lack of scalp hair. Furthermore, the severity of WH phenotype was also variable among individuals. Such variations in phenotype were detected even within a single family (Shimomura et al.
, 2008c). Similarly, although all affected individuals in the Guyanese families commonly had WH at birth, they show variations in severity with aging. In family A, the elder affected individual shows a severe hypotrichosis (), while the younger affected individual exhibits a relatively mild phenotype. In Family B, both affected individuals showed overlapping phenotypes between WH and hypotrichosis (), but the degrees of WH are different between them. Interestingly, both affected individuals in Family B also have keratosis pilaris-like eruption on their extremities and abdomen (), which may be a non-specific sign seen in many forms of hypotrichosis, atrichia, and fragile hair disorders (Zlotogorski et al., 2002
; Weiss et al., 2004
; Zlotogorski et al., 2006
Inherited disorders of lipid metabolism leading to permeability barrier abnormalities of the skin drive pathophysiology of scaling disorders with effects on proliferation and inflammation (Elias et al., 2008
). Whether lipid processing defects affect hair structure by altering protein expression is less well studied. The unusual physical properties of WH, including a reported characteristic shape, could plausibly reflect altered protein composition or structural organization. However, present data indicate that predominant proteins detected were affected little, if at all, by the LIPH
gene defect. Thus, the unusual properties of the hair are likely due simply to defects in the lipid component.
Quantitating relative protein amounts in cross-linked complexes is an incompletely resolved challenge. Nevertheless, limited quantitative comparisons of given proteins among different samples appear feasible on the basis of normalized spectral abundance, where the numbers of peptides detected are anticipated to be proportional to protein length (Zybailov et al., 2006
). While only a rough approximation, the exponentially modified protein abundance index (emPAI) approach used presently has an empirical basis (Ishihama et al., 2005
; Ishihama et al., 2008
). Such estimates are likely to improve as more targeted measurements of select “proteotypic” peptides of specific proteins are developed (Deutsch et al., 2008
). While a more detailed study would be required to detect subtle differences in protein content or to identify changes among less prevalent proteins, our results suffice to rule out major changes in protein expression as a characteristic feature of the WH syndrome. By contrast, subtypes of WH connected with more serious defects could display such changes that reflect downstream effects of the genetic lesion. In that case, proteomic analysis could help in their classification.
We and others have recently shown that mutations in the P2RY5
gene underlie ARWH/hypotrichosis (Pasternack et al., 2008
; Shimomura et al., 2008b
). The clinical features of affected individuals with P2RY5
mutations are indistinguishable from those with LIPH
mutations. The LIPH
gene encodes a phospholipase A1 family member and is a key enzyme in the synthesis of lysophosphatidic acid (LPA) (Sonoda et al., 2002
), which is an extracellular mediator of many biological functions and is known to promote hair growth in vivo (Takahashi et al., 2003
). P2Y5 has recently been shown to be a LPA receptor (Pasternack et al., 2008
), and furthermore, we have demonstrated that the expression of P2Y5 partially overlaps with that of LIPH in HFs in vivo (Shimomura et al.
, 2008c). These data underscore a crucial role of the LIPH/LPA/P2Y5 signaling pathway in hair growth in humans.