Variant <i>PADI3</i> in Central Centrifugal Cicatricial Alopecia

Malki, Liron; Sarig, Ofer; Romano, Maria-Teresa; Méchin, Marie-Claire; Peled, A.; Pavlovsky, Mor; Warshauer, Emily; Samuelov, Liat; Uwakwe, Laura N; Briskin, Valeria; Mohamad, Janan; Gat, Andrea; Isakov, Ofer; Rabinowitz, Tom; Shomron, Noam; Adir, Noam; Simon, Michel; McMichael, Amy J.; Dlova, Ncoza C.; Betz, Regina C.; Sprecher, Eli

doi:10.1056/nejmoa1816614

Cited by 114 publications

(100 citation statements)

References 43 publications

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“…CCCA is a lymphocytic scarring alopecia that is likely associated with environmental and genetic etiologies. A recent study demonstrated that mutations in the PADI3 gene may be associated with CCCA . The PADI3 gene codes for a peptidyl arginine deiminase that converts arginine into citrulline and plays an important role in hair shaft structure and IRS biology.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the inflammatory features of central centrifugal cicatricial alopecia

et al. 2020

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Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia that primarily affects women of African descent. Although histopathological features of CCCA have been described, the pathophysiology of this disease remains unclear. To better understand the components of CCCA pathophysiology, we evaluated the composition of the inflammatory infiltrate, the distribution of Langerhans cells (LCs), and the relationship between fibrosis and perifollicular vessel distribution. Our data indicate that CCCA is associated with a CD4-predominant T-cell infiltrate with increased LCs extending into the lower hair follicle. Fibroplasia associated with follicular scarring displaces blood vessels away from the outer root sheath epithelium. These data indicate that CCCA is an inflammatory scarring alopecia with unique pathophysiologic features that differentiate it from other lymphocytic scarring processes.

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Section: Discussionmentioning

confidence: 99%

Characterization of the inflammatory features of central centrifugal cicatricial alopecia

et al. 2020

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“…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. 7 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 originand herein lies a challenge with the interpretation of these data.…”

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confidence: 99%

“…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%).…”

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confidence: 99%

“…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.…”

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confidence: 99%

“…Several investigators might argue, therefore, that although the Malki et al . data are helpful in improving understanding of CCCA, there remains the possibility that the findings offer only a preliminary insight and that further investigative methods and appropriate study designs more suited to the molecular dissection of CCCA are now essential. The potential added value of whole exome sequencing in complex traits has been demonstrated already in disorders such as ulcerative colitis .…”

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PADI3 , hair disorders and genomic investigation

2019

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Low-Dose Metformin and Profibrotic Signature in Central Centrifugal Cicatricial Alopecia

Bao,

Qadri,

Gadre

et al. 2024

JAMA Dermatol

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ImportanceCentral centrifugal cicatricial alopecia (CCCA) is a scarring alopecia predominantly affecting Black female individuals. Current conventional treatments target inflammation but not the underlying fibrotic processes, often leading to permanent hair loss.ObjectiveTo investigate the associations of low-dose oral metformin, an antidiabetic medication with antifibrotic properties, with clinical symptoms and scalp gene expression patterns in patients with CCCA.Design, Setting, and ParticipantsThis retrospective clinical case series and transcriptomic analysis included patients treated at a single tertiary academic medical center between January 2023 and March 2024. All patients had biopsy-confirmed CCCA refractory to standard treatments. Transcriptomic analysis was performed on patients with previously banked, paired scalp biopsies before and after treatment with adjuvant metformin for at least 6 weeks.ExposureExtended-release metformin, 500 mg, once daily was added to participants’ baseline CCCA treatment regimens.Main Outcomes and MeasuresClinical assessments included pruritus, inflammation, scalp resistance, and hair regrowth. Gene expression profiling via bulk RNA sequencing analysis evaluated differential gene expression and pathway enrichment.ResultsA total of 12 Black female participants were included in the study, and transcriptomic analysis was performed in 4 participants. After at least 6 months of metformin treatment, 9 participants experienced improvement in disease, including scalp pain, inflammation, and/or pruritus, and 6 demonstrated clinical evidence of hair regrowth. The addition of metformin led to reversal of many prominent gene pathways previously identified in CCCA. Transcriptomic analysis revealed upregulation of pathways and genes (keratin-associated proteins [KRTAPs]) involved in keratinization, epidermis development, and the hair cycle (absolute log2-fold change &gt; 4), with concomitant downregulation of fibrosis-related pathways and genes (eg, MMP7, COL6A1) (fold change &gt;1.5; all false discovery rate &lt;.05). Gene set analysis showed reduced expression of helper T cell 17 and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and KRTAPs after metformin treatment.Conclusions and RelevanceIn this case series of patients with treatment-refractory CCCA, low-dose oral metformin was associated with symptomatic improvement and dual modulation of gene expression, stimulating hair growth pathways while suppressing fibrosis and inflammation markers. These findings provide a rationale for future clinical trials studying metformin as a targeted therapy for CCCA and other cicatricial alopecias.

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Variant PADI3 in Central Centrifugal Cicatricial Alopecia

Cited by 114 publications

References 43 publications

Characterization of the inflammatory features of central centrifugal cicatricial alopecia

Characterization of the inflammatory features of central centrifugal cicatricial alopecia

PADI3 , hair disorders and genomic investigation

Low-Dose Metformin and Profibrotic Signature in Central Centrifugal Cicatricial Alopecia

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