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, 88 (6), 788-795

Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature

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Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature

Rami Abou Jamra et al. Am J Hum Genet.

Abstract

Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42(∗)), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs(∗)20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex.

Figures

Figure 1
Figure 1
Genetic Analysis of Family ID01 (A) Pedigree of the family. (B) Electrophoregrams illustrating the c.487_488insTAT, p.Glu163_Ser739delinsVal variant in exon 5 of AP4B1. Data are shown for homozygous affected individuals, heterozygous healthy parents, and homozygous wild-type healthy siblings. (C) Quantitative RT-PCR analysis of AP4B1 mRNA. AP4B1 expression in fibroblast cells from three controls and from patient IV-2. Data are normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Means ± standard deviation are given (n = 3 independent experiments). ∗∗∗p value of < 0.01 (Student's test) for the difference of expression. ∗∗p value of < 0.05 (Student's test) for the difference of expression.
Figure 2
Figure 2
Genetic Analysis of Family MR061 (A) Pedigree of family; arrows indicate index. Family MR061 is large with multiple affected individuals with variable phenotypes. Grey symbols denote individuals in whom clinical presentation is markedly different and who have no AP4S1 mutation (heterogeneity within the family). (B) Electropherograms illustrating the mutation in exon 2 of AP4S1. (C) Facial appearance of affected individuals with discreet remarkable facial gestalt, including a prominent and bulbous nose, a wide mouth, and coarse features and photographs of lower limbs with foot deformity and decreased muscle mass of the shanks.
Figure 3
Figure 3
Genetic Analysis of Family MR071 (A) Pedigree of family MR071. (B) Representative sequence traces from cDNA showing skipping of exon 5. (C) Facial appearance of affected individuals includes discreet remarkable facial gestalt with prominent and bulbous nose, wide mouth, and coarse features. Also shown are photographs of the lower limbs with foot deformity and decreased muscle mass of the shanks. (D) RT-PCR products of mRNA from homozygous affected individuals, heterozygous healthy parents, and homozygous wild-type healthy siblings; the expected size from the normal AP4E1 allele (512 bp) as well as a smaller band corresponding to aberrant splicing of the mutated allele with skipping of exon 5 (389 bp) is shown.

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