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

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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, Orianne Philippe, Annick Raas-Rothschild, Sebastian H. Eck, Elisabeth Graf, Rebecca Buchert, Guntram Borck, Arif Ekici, Felix F. Brockschmidt, Markus M. Nöthen, Arnold Munnich, Tim M. Strom, Andre Reis, Laurence Colleaux The American Journal of Human Genetics Volume 88, Issue 6, Pages 788-795 (June 2011) DOI: 10.1016/j.ajhg.2011.04.019 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2011 88, 788-795DOI: (10.1016/j.ajhg.2011.04.019) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2011 88, 788-795DOI: (10.1016/j.ajhg.2011.04.019) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2011 88, 788-795DOI: (10.1016/j.ajhg.2011.04.019) Copyright © 2011 The American Society of Human Genetics Terms and Conditions