An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome

Abstract

The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.

Molecular Basis for the Interaction Between AP4 β4 and its Accessory Protein, Tepsin

“…A β4 knockout mouse exhibits missorting of low‐density lipoprotein (LDL), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) and δ2 glutamate receptors from somatodendrites to axons but shows no further significant anatomical abnormalities. In contrast, human patients with mutations in any one of the four AP4 subunits suffer from a severe ‘AP4 deficiency syndrome’ characterized by early onset of severe intellectual disability, growth retardation, stereotypic laughter, progressive spasticity and an inability to walk (, reviewed in ). AP4 thus likely plays a key role in neurological development and function, but the underlying mechanism remains unclear.…”

Characterization of patients referred for non‐specific intellectual disability testing: the importance of autosomal genes for diagnosis

“…A frameshift mutation, c.311_312delinsC, and missense variant, c.577G > A (p.Val193Ile) were identified in the AP4B1 gene in patient 9, a 4‐year‐old African American male. Mutations in AP4B1 have been described in only three families with ID and progressive spastic paraplegia . The previously identified mutations (c.487_488insTAT, c.664delC and c.1160_1661delCA) have all been identified in the homozygous state in affected individuals of Middle Eastern origin.…”

Structure and evolution of ENTH and VHS/ENTH‐like domains in tepsin

“…Recently, ENTH domains in yeast Ent1 and zebrafish epsin1 have been reported to bind very weakly to ubiquitin (~2 mM K D ). 37 We thus tested whether recombinant tENTH could interact with 15 N-labeled mono-ubiquitin in an NMR chemical shift perturbation experiment, because NMR is the most sensitive method for detecting weak interactions. We detect no interaction between tENTH and ubiquitin ( Figure S2B).…”

“…region to axons 13 but shows no significant anatomical abnormalities. In contrast, human patients with mutations in any of the 4 AP4 subunits [14][15][16][17] suffer from the hereditary spastic paraplegias, 14 (reviewed in 18 ). AP4 thus plays a key role in neurological development and function, but the underlying mechanism for this role remains unclear.…”