Identification of compound heterozygous mutations in <i>AP1B1</i> leading to the newly described recessive keratitis–ichthyosis–deafness (KIDAR) syndrome

Abstract

Dear Editor, Recently, mutations in adaptor-related protein complex 1 subunit beta 1 (AP1B1) have been identified as the cause of a new form of syndromic ichthyosis, which is characterized by neonatal onset of ichthyosis, erythroderma and deafness accompanied by failure to thrive and developmental delay.1, 2 In adulthood, keratitis has been diagnosed as well.1 Based on the observed phenotype and the autosomal recessive mode of inheritance, the disease has been classified as a keratitis–ichthyosis–deafness syndrome (KIDAR; OMIM 242150). In this letter, we describe an additional case of KIDAR caused by AP1B1 mutations, including one novel missense mutation. We also show the molecular consequences of the mutations and define the main features of this new syndrome. The girl was born at term without a collodion membrane or persisting dryness of skin. At the age of 2 weeks, she developed an ichthyosiform erythroderma and chronic, severe pruritus (Figure 1a). Global developmental retardation and failure to thrive were observed, as well as thickened plantar surface (Figure 1b), bilateral ectropion and partial alopecia. The nails were unremarkable. Her complete blood count with differential, serum very long-chain fatty acids, and serum levels of iron, zinc, copper and ceruloplasmin were normal. At the age of 31 months (Figure 1c), her skin was dry with generalized scaling, most pronounced on the face and the extremities, with light erythematous patches without erosions, blistering or other signs of skin fragility. Dermatological treatment consisted of frequent emollient applications and short courses of topical corticosteroids or pimecrolimus ointment. Despite chronic diarrhoea she caught up with growth retardation and showed less severe failure to thrive. Meanwhile, she had been diagnosed with bilateral deafness and had developed moderate photophobia. Other neurological, ocular or dental anomalies were not present. The histopathology of the skin biopsy presents epidermal thickening and hyperkeratosis (Figure 1d). The patient underwent extensive diagnostic investigations excluding a broad range of cutaneous and syndromal diseases potentially underlying infantile erythroderma.3 Whole-exome sequencing and subsequent Sanger sequencing in our patient revealed compound heterozygous mutations in AP1B1 (c.322C>T, p.Arg108Trp and c.2254delC, p.Leu752Serfs*26) (Figure 1e), while each of the healthy, nonconsanguineous parents carried one of the variants in a heterozygous state. Five recently described cases with AP1B1 mutations and our index patient share almost the same phenotype including ichthyosis, erythroderma, deafness and developmental delay. Both the phenotypic similarities and the c.2254delC mutation already described in this context (referred to a different transcript) support our findings that the variants detected in AP1B1 cause the phenotype of our patient.1, 2 Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.1 Molecular examination demonstrated complete loss of AP1B1 in the epidermis (formalin-fixed paraffin-embedded sections) and isolated keratinocytes from our patient’s skin (Figure 1f, g). On the genetic level, the frameshift mutation (c.2254delC) induces a premature stop codon (p.Leu752Serfs*26) activating nonsense-mediated mRNA decay. The missense mutation (c.322C>T, p.Arg108Trp) affects a highly conserved residue (phyloP/phastCons) within the putative protein-binding region of AP1B1 (Figure 1h).4 In silico analysis predicts the mutation to be deleterious (SIFT), probably damaging (PolyPhen) and disease causing (MutationTaster). Reverse-transcriptase polymerase chain reaction from isolated keratinocytes detected the missense mutation but not the frameshift mutation, confirming the presumed mRNA degradation from the allele carrying the frameshift mutation (Figure 1i). This is further supported by the presence of a homozygous single-nucleotide polymorphism (c.2268G>A) according to sequenced mRNA, whereas Sanger sequencing of the patient’s blood detected the single-nucleotide polymorphism in a heterozygous form. The allele carrying the missense mutation is successfully transcribed into mRNA, but no protein is detected in the epidermis or keratinocytes. We assume protein degradation due to potential conformational change of the protein, resulting in protein instability and/or failure of protein–protein interaction. For now, this remains unresolved. AP1B1 encodes the large β-subunit of the adaptor protein (AP)1 complexes, which play an important role in polarized vesicular transport in eukaryotic cells. AP1 is involved in the formation of clathrin-associated vesicles and the selection of cargo proteins in the trans-Golgi network and/or endosomes for basolateral transport.5, 6 The pathophysiological causes of KIDAR have not yet been clarified, but previous studies have indicated that cell-polarity defects may cause at least deafness and hyperproliferation,2, 7 whereas epidermal consequences remain to be investigated. In summary, we demonstrate that compound heterozygous mutations in AP1B1 can induce complete loss of protein in human epidermis and may cause the symptoms described in our index patient. In addition to expanding the extremely short list of diagnosed AP1B1-deficient patients and specification of the main clinical features of this new syndrome, we describe the molecular consequences of AP1B1 mutations at the mRNA and protein levels. the authors would like to thank Professor Dr G. B. Stark and Dr Z. Kalash from the department of Plastic Surgery, Medical Center, University of Freiburg, as well as the donors for the provision of control skin samples and Dr Sabine Jägle and Julia Kopp from our laboratory for critical discussion. We further thank Dr Susan Cure for her help in correcting the manuscript. We also wish to gratefully thank our index patient and her family for the cooperation and for providing DNA samples and/or skin biopsy material. Open Access funding enabled and organized by ProjektDEAL. Julia Vornweg: Conceptualization (lead); Formal analysis (supporting); Investigation (equal); Methodology (lead); Project administration (lead); Supervision (lead); Validation (lead); Visualization (lead); Writing-original draft (lead); Writing-review & editing (lead). Selina Gläser: Investigation (equal); Writing-original draft (supporting). Mehwish Ahmad-Anwar: Investigation (equal). Andreas David Zimmer: Data curation (equal); Formal analysis (equal). Marius Kuhn: Formal analysis (equal); Investigation (supporting). Steffen Hörer: Investigation (supporting). Georg Christoph Korenke: Investigation (equal); Writing-review & editing (equal). Julia Grothaus: Investigation (equal). H. Ott: Investigation (equal); Writing-original draft (equal); Writing-review & editing (equal). Judith Fischer: Conceptualization (lead); Data curation (equal); Formal analysis (equal); Funding acquisition (lead); Investigation (equal); Methodology (equal); Project administration (lead); Resources (lead); Supervision (lead); Writing-original draft (lead); Writing-review & editing (lead).

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