British Journal of Dermatology | 2019
PADI3, hair disorders and genomic investigation
Abstract
Back in 1973, Dupr e et al. described a new hair shaft abnormality resulting in hair of an unusual texture and appearance. This disorder became known as uncombable hair syndrome (UHS), also known as ‘spun glass hair syndrome’, ‘pili trianguli et canaliculi’ or ‘cheveux incoiffables’. Clinically, the hair often appeared fair, dry, frizzy and resistant to being combed flat, although the phenotype typically improved later in childhood. Some cases occurred sporadically but in others there were autosomal dominant or autosomal recessive inheritance patterns. In 2016, Basmanav et al. used whole exome sequencing to identify the molecular basis of UHS. Looking for rare loss-offunction variants they identified biallelic mutations in three genes: PADI3, TGM3 and TCHH in a total of 11 children. The two enzymes peptidyl arginine deiminase 3 (PADI3) and transglutaminase 3 (TGM3) are responsible for post-translational protein modifications and, along with their target structural protein trichohyalin (TCHH), are involved in hair shaft formation. Of note, PADI3 represents a member of the peptidyl arginine deiminase family of enzymes that catalyse the post-translational deimination of proteins by converting L-arginine residues into citrulline. Supportive cell culture experiments, tri-dimensional protein models and scanning electron microscopy collectively demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins and helped elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology. Regarding the process of identifying the three candidate genes in UHS, whole exome sequencing was the ideal investigative method. Whole exome sequencing is a genomic technique for sequencing the protein-coding region of genes in the genome; there are about 180 000 exons which make up ~1% of the human genome. Whole exome sequencing is therefore an efficient way to identify very rare genetic variants that are present in a small number of individuals and that underlie rare Mendelian diseases. Roll on to 2019 and PADI3 mutations have now been implicated in another hair disorder, central centrifugal cicatricial alopecia (CCCA). CCCA represents the most common cause of scarring alopecia, predominantly affecting the central scalp, in women of African descent. In terms of its aetiology, mechanical hair straightening, use of chemical relaxers and heat have all been implicated as possible causative factors in CCCA and the condition is often referred to as ‘hot comb alopecia’. Such trigger factors, however, may be absent in some cases, adding to the complexity of the aetiology of CCCA. Despite the absence of accurate population studies, the incidence of CCCA has been reported to be 2 7–5 6% with an average age of 36 years at presentation. Familial CCCA is very rare and even the reported pedigrees have been mostly limited to two generations, which could simply represent segregation of common variation in a common disease rather than strong supportive evidence for Mendelian inheritance. To investigate a possible genetic basis to CCCA, Malki et al. have used whole exome sequencing in a study of 16 African women with CCCA and identified four heterozygous alleles (one splice site, three missense) in PADI3 in five individuals. Extending the cohort, the authors reported a total of six PADI3 predicted missense and splice disrupting alleles in 14 of 58 patients (24%). Evaluation of whether this observation represents an elevation in protein disrupting alleles, however, was limited to a comparison with observations of PADI3 alleles in 58 control participants of African origin – and herein lies a challenge with the interpretation of these data. Over the past 20 years of genetics research, investigators have developed and applied a rigorous framework for the evaluation of genetic associations. This framework, including control for population stratification and rigorous multiple testing thresholds, has dramatically reduced the reporting of spurious associations in the literature. While the reported PADI3 findings in CCCA are intriguing, further experimentation is required to ensure that this association is robust and not confounded by population stratification. Aside from the genetics, the Malki et al. study also included supportive data showing reduced expression of PADI3 protein in CCCA scalp skin, along with in vitro studies of mutant PADI3 protein aggregation and decreased enzyme activity. These observations cannot be directly connected to the characteristic clinicopathological features of CCCA, including the premature desquamation of the inner root sheath, the dislocation and eventual loss of hair shafts, and perifollicular inflammation and fibrosis leading to the scarring phenotype, but the data do provide fresh insight into the pathobiology of CCCA. Indeed, despite the reservations about the genetic association methodology, the authors may well be correct in highlighting PADI3 as an important protein in CCCA. For most common diseases where there is evidence of heritability, but the majority of affected individuals lack any clear evidence for Mendelian inheritance, association studies provide a framework to identify variants with effect sizes that do not result in clear familial segregation. Such studies require the ascertainment of large numbers of cases and controls to ensure they are sufficiently powered to detect variants robustly with expected moderate effect sizes. A genome-wide association