A novel homozygous AP4B1 mutation in two brothers with AP‐4 deficiency syndrome and ocular anomalies

Adaptor protein complex‐4 (AP‐4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP‐4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, con...

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Published inAmerican journal of medical genetics. Part A Vol. 176; no. 4; pp. 985 - 991
Main Authors Accogli, Andrea, Hamdan, Fadi F., Poulin, Chantal, Nassif, Christina, Rouleau, Guy A., Michaud, Jacques L., Srour, Myriam
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.04.2018
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Abstract Adaptor protein complex‐4 (AP‐4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP‐4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms “AP‐4 deficiency syndrome” for this clinically recognizable phenotype. Using whole‐exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP‐4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP‐4 deficiency, speculating on a possible role of AP‐4 complex in eye development.
AbstractList Adaptor protein complex‐4 (AP‐4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP‐4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms “AP‐4 deficiency syndrome” for this clinically recognizable phenotype. Using whole‐exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP‐4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP‐4 deficiency, speculating on a possible role of AP‐4 complex in eye development.
Author Accogli, Andrea
Poulin, Chantal
Nassif, Christina
Michaud, Jacques L.
Srour, Myriam
Rouleau, Guy A.
Hamdan, Fadi F.
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Issue 4
Keywords AP-4 complex
spastic tetraplegia
cataract
AP-4 deficiency
AP4B1
Horner syndrome
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Snippet Adaptor protein complex‐4 (AP‐4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting...
Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting...
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SubjectTerms Adaptor Protein Complex 4 - genetics
Adolescent
AP4B1
AP‐4 complex
AP‐4 deficiency
Atrophy
Brain - abnormalities
cataract
Cataracts
Child
Epilepsy
Eye
Eye Abnormalities - diagnosis
Eye Abnormalities - genetics
Face
Facies
Genetic Association Studies
Homozygote
Horner syndrome
Humans
Innervation
Magnetic Resonance Imaging
Male
Microcephaly
Mutation
Optic nerve
Pedigree
Phenotype
Phenotypes
Severity of Illness Index
Siblings
spastic tetraplegia
Spasticity
Substantia alba
Sympathetic nervous system
Syndrome
Title A novel homozygous AP4B1 mutation in two brothers with AP‐4 deficiency syndrome and ocular anomalies
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