John Y.W. Lee

Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia.

Mutations in ceramide biosynthesis pathways have been implicated in a few Mendelian disorders of keratinization, although ceramides are known to have key roles in several biological processes in skin and other tissues. Using whole-exome sequencing in four probands with undiagnosed skin hyperkeratosis/ichthyosis, we identified compound heterozygosity for mutations in KDSR, encoding an enzyme in the de novo synthesis pathway of ceramides. Two individuals had hyperkeratosis confined to palms, soles, and anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Thrombocytopenia was present in all patients. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all patients, resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study shows that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology.

Familial progressive hyper- and hypopigmentation and malignancy in two families with new mutations in KITLG.

Familial progressive hyper‐ and hypopigmentation (FPHH) is an autosomal dominant skin condition presenting in childhood with generalized macular dyspigmentation, usually reported in patients of East Asian origin. It overlaps phenotypically with other dyschromatoses, but can now be distinguished by mutations in the KIT ligand gene (KITLG).

Congenital Anonychia and Uncombable Hair Syndrome: Coinheritance of Homozygous Mutations in RSPO4 and PADI3

Citing this paper Please note that where the full-text provided on Kings Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publishers definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publishers website for any subsequent corrections.

Ichthyosis follicularis, atrichia, and photophobia syndrome associated with a new mutation in MBTPS2

Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome (OMIM 308205) is a rare X‐linked genetic disorder. Mutations in MBTPS2 underlie IFAP syndrome, with 19 different mutations reported to date. Keratosis follicularis spinulosa decalvans (KFSD) is an allelic disorder that results from a single recurrent mutation, p.Asn508Ser. We report a case from the UK of IFAP syndrome resulting from a new mutation, p.Asn508Thr, emphasizing the significant overlap between IFAP and KFSD at both the molecular and clinical levels. An area of alopecia on the scalp of the probands mother was also noted, suggesting lyonization.

Advances in the genetic understanding of hypohidrotic ectodermal dysplasia

ABSTRACT Introduction: Ectodermal dysplasia refers to the abnormal development of two or more embryological elements that give rise to skin, hair, teeth, and sweat glands. Clinically, ectodermal dysplasia can be phenotypically diverse with >200 different syndromes documented in the literature based on ascertainment of particular developmental anomalies. Area covered: The most common subtype is hypohidrotic ectodermal dysplasia which occurs in ~7 per 10,000 live births. Most cases of hypohidrotic ectodermal dysplasia are X-linked, although autosomal dominant and autosomal recessive cases may occur, and mutations in four genes have been implicated in this form of ectodermal dysplasia: EDA, EDAR, EDARADD, and WNT10A. Expert opinion: The protean nature of ectodermal dysplasia makes clinical or mechanistic classification challenging but identification of causative gene pathologies in ~30% of all ectodermal dysplasias, including the vast majority of hypohidrotic ectodermal dysplasia cases, has improved diagnostic precision, made DNA-based prenatal diagnosis possible, and advanced translational research, including the clinical testing of recombinant proteins targeting the inherent molecular pathology in a subgroup of affected individuals.

Further evidence for genotype-phenotype disparity in Griscelli syndrome

First described in 1978, Griscelli syndrome (GS) is a rare autosomal recessive disorder featuring pigmentary dilution of hair and skin.1 GS is caused by mutations in any of three genes encoding a tripartite protein complex essential for melanosome transport.2 GS1 (MIM214450) presents as hypomelanosis with primary neurological defects and is caused by mutations in MYO5A,3 and which also may be the same entity as Elejalde syndrome (MIM256710).4 This article is protected by copyright. All rights reserved.

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45

SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole‐exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as uncomplicated or complicated HSP.