MEDNIK‐like syndrome due to compound heterozygous mutations in <i>AP1B1</i>

Ito, Yoichi; Takeichi, Takuya; Igari, Shohei; Mori, Tatsuhiko; Ono, Atsushi; Suyama, Kazuhide; Takeuchi, So; Muro, Yoshinao; Ogi, Tomoo; Yamamoto, Toshiyuki; Akiyama, Masashi

doi:10.1111/jdv.17098

Cited by 7 publications

(2 citation statements)

References 5 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 More recently, authors reported a single G insertion in a stretch of 8 consecutive G's between nucleotides 356 and 365 in exon 4, encoding a premature stop codon; these patients had a multisystemic presentation. 9 Interestingly, pathogenic variants, including homozygous deletions 10 and compound heterozygous 11 variants, in another subunit of the adaptor-related protein complex, AP1B1, can also present with a IDEDNIK-like syndrome with ichthyosis, enteropathy, and developmental delay. These syndromes fall into the group of epithelial structure, trafficking, and polarity according to the most recent classification of monogenic intestinal epithelial disorders.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant

Namjoshi

Niehaus

et al. 2023

Pediatr Dev Pathol

View full text Add to dashboard Cite

Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6 months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant

Namjoshi

Niehaus

et al. 2023

Pediatr Dev Pathol

View full text Add to dashboard Cite

show abstract

“…, 2019 ; Boyden et al. , 2019 ; Ito et al. , 2021 ) subunits, however, do have skin manifestations, probably owing to the requirement of AP-1 for polarized sorting in epithelial cells ( Fölsch et al.…”

Section: Discussionmentioning

confidence: 99%

The adaptor protein chaperone AAGAB stabilizes AP-4 complex subunits

Mattera

Pace

Bonifacino

2022

MBoC

View full text Add to dashboard Cite

Adaptor protein 4 (AP-4) is a heterotetrameric complex composed of ε, β4, μ4 and σ4 subunits that mediates export of a subset of transmembrane cargos, including autophagy protein 9A (ATG9A), from the trans-Golgi network (TGN). AP-4 has received particular attention in recent years because mutations in any of its subunits cause a complicated form of hereditary spastic paraplegia (HSP or SPG) referred to as “AP-4-deficiency syndrome.” The identification of proteins that interact with AP-4 has shed light on the mechanisms of AP-4-dependent cargo sorting and distribution within the cell. However, the mechanisms by which the AP-4 complex itself is assembled have remained unknown. Herein, we report that the alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34) binds to and stabilizes the AP-4 ε-and σ4 subunits, thus promoting complex assembly. The importance of this binding is underscored by the observation that AAGAB-knockout cells exhibit reduced levels of AP-4 subunits and accumulation of ATG9A at the TGN like those in cells, mice, or patients with mutations in AP-4-subunit genes. These findings demonstrate that AP-4 assembly is not spontaneous but AAGAB-assisted, thus contributing to the understanding of an adaptor protein complex that is critically involved in development of the central nervous system.

show abstract

Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion

Rackova,

Mattera,

Svaton

et al. 2024

J Mol Med

View full text Add to dashboard Cite

MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. Key messages A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.

show abstract

MEDNIK‐like syndrome due to compound heterozygous mutations in AP1B1

Abstract: 2 Harries MJ, Meyer K, Chaudhry I et al. Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.

Cited by 7 publications

References 5 publications

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant

The adaptor protein chaperone AAGAB stabilizes AP-4 complex subunits

Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion

Contact Info

Product

Resources

About