Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia

Abstract

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the b subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 b subunit is lost, and the g subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.

Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection

“…As a result, entry factors like ACE2 and TMPRSS2 may be mislocalized in AP1 LOF cells, resulting in decreased viral entry. Disrupting the AP1 complex in vivo has also been demonstrated to result in altered epithelial cell-cell junctions and cell polarity, resulting in a hyperproliferative state (Bonifacino, 2014; Boyden et al, 2019; Hase et al, 2013). Given our data suggesting a critical role for cell proliferation regulation and cell-cell junction proteins like E-cadherin (CDH1) in SARS-CoV-2 infection, perturbation of these pathways in AP1 LOF cells may also explain their resistance to SARS-CoV-2 infection (Bonifacino, 2014; Boyden et al, 2019; Castillon et al, 2018; Hase et al, 2013; Takahashi et al, 2011).…”

Clinical, etiopathogenic, and therapeutic aspects ofKIDsyndrome

“…There are also reports of other ocular, dental, hepatic, and metabolic defects. [17][18][19][20][21][22] This subtype is caused by homozygous mutation in the AP1B1 gene at chromosomal region 22q12.2, as p.Glu14Argfs*5, and a deletion of 75 kb that removes the tentative promoter as well as the first two exons of AP1B1 gene, so it is predicted to be a null at the protein level 17 and other homozygous mutation as p.Glu792*, 18 or compound heterozygous in a male patient as p.Cys144Arg inherited from his unaffected mother and p.Leu779Serfs*26 inherited from his unaffected father. 18…”

“…This entity is clinically characterized by ichthyosiform erythroderma, profound sensorineural deafness, vascularizing keratitis, developmental delay, and failure to thrive. There are also reports of other ocular, dental, hepatic, and metabolic defects 17‐22 …”

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

“…A large community of clinicians and scientists continues to identify novel genes and variants for syndromic and nonsyndromic hearing loss. In the past two years alone, variants within novel hearing loss genes including SLC9A3R1, ANLN, FOXF2, TOP2B, PLS1, PISD, CLRN2, AP1B1, SCD5, GGPS1, SLC12A2, THOC1 and GREB1L were identified in patients of various ethnicities [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. To date, some of these genes remain candidates that require replication in additional hearing loss families and patients [6,9,14,19].…”