Heterozygous frameshift mutation in keratin 5 in a family with G alli– G alli disease

Abstract

BackgroundReticulate pigmentary disorders include the rare autosomal dominant Galli–Galli disease (GGD) and Dowling–Degos disease (DDD). Clinical diagnosis between some of the subtypes can be difficult due to a degree of overlap between clinical features, therefore analysis at the molecular level may be necessary to confirm the diagnosis.ObjectivesTo identify the underlying genetic defect in a 48-year-old Asian-American woman with a clinical diagnosis of GGD.MethodsHistological analysis was performed on a skin biopsy using haematoxylin–eosin staining. KRT5 (the gene encoding keratin 5) was amplified from genomic DNA and directly sequenced.ResultsThe patient had a history of pruritus and hyperpigmented erythematous macules and thin papules along the flexor surfaces of her arms, her upper back and neck, axillae and inframammary areas. Hypopigmented macules were seen among the hyperpigmentation. A heterozygous 1-bp insertion mutation in KRT5 (c.38dupG; p.Ser14GlnfsTer3) was identified in the proband. This mutation occurs within the head domain of the keratin 5 protein leading to a frameshift and premature stop codon.ConclusionsFrom the histological findings and mutation analysis the individual was identified as having GGD due to haploinsufficiency of keratin 5.

Mutations inPOGLUT1in Galli–Galli/Dowling–Degos disease

“…In light of substantial clinical, histological and mutational overlap between GGD and DDD, they are considered to belong to the same entity 2, 3. Mutations in KRT5 (encoding keratin 5) have been associated with GGD/DDD since 2006 2, 3, 4, 5. With the development of whole‐exome sequencing, mutations in POFUT1 (encoding protein O ‐fucosyltransferase 1)6, 7 and POGLUT1 (encoding protein O ‐glucosyltransferase 1)8 have been shown to underlie some cases of GGD/DDD.…”

Confirmation of the role of aKRT5mutation and successful management of skin lesions in a patient with Galli-Galli disease

“…Most cases were reported from Germany, in which c.418dupA was described as the most common mutation in patients with acantholytic DDD. Further mutations were described in Spanish, Arabic, Asian‐American, Chinese and Indian patients . In some cases, acantholysis was not observed, and it has also been reported that acantholysis may not necessarily be present at all times or at all anatomical sites .…”

“…Further mutations were described in Spanish, Arabic, Asian‐American, Chinese and Indian patients . In some cases, acantholysis was not observed, and it has also been reported that acantholysis may not necessarily be present at all times or at all anatomical sites . In many cases, both from Europe and Asia, an association between DDD/GGD and a KRT5 mutation could not be detected.…”

“…Later they revised their former report, and concluded that this mutation is linked to the acantholytic variant of DDD1, known as GGD . As acantholysis may not be seen in every slide, this explains its absence in some reports with confirmed genetic mutation …”

“…acantholysis may not necessarily be present at all times or at all anatomical sites. 3,5 In many cases, both from Europe and Asia, an association between DDD/ GGD and a KRT5 mutation could not be detected. Recently, novel mutations in the POGLUT1 and POFUT1 genes of the Notch signalling pathway have also been identified as causative of DDD in German and Chinese familial and sporadic cases.…”