title: KCNA4deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability.
abstract: BACKGROUND
  Voltage-gated potassium channels are highly diverse proteins representing the most complex class of voltage-gated ion channels from structural and functional perspectives. Deficiency of these channels usually results in various human disorders.
  
  
  OBJECTIVE
  To describe a novel autosomal recessive syndrome associated withKCNA4deficiency leading to congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder.
  
  
  METHODS
  We used SNP arrays, linkage analyses, autozygosity mapping, whole-exome sequencing, RT-PCR and two-electrode voltage-clamp recording.
  
  
  RESULTS
  We identified a missense variant (p.Arg89Gln) inKCNA4in four patients from a consanguineous family manifesting a novel syndrome of congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder. The variant was fully segregated with the disease and absent in 747 ethnically matched exomes.Xenopusoocytes were injected with human Kv1.4 wild-type mRNA, R89Q and WT/R89Q channels. The wild type had mean current amplitude that was significantly greater than those recorded from the cells expressing the same amount of mutant mRNA. Co-expression of the wild type and mutant mRNAs resulted in mean current amplitude that was significantly different from that of the wild type. RT-PCR indicated thatKCNA4is present in mouse brain, lens and retina.KCNA4interacts with several molecules including synaptotagmin I,DLG1andDLG2.The channel co-localises with cholinergic amacrine and rod bipolar cells in rats and is widely distributed in the central nervous system. Based on previous studies, the channel is highly expressed in outer retina, rod inner segments, hippocampus and concentrated in axonal membranes.
  
  
  CONCLUSIONS
  KCNA4(Kv1.4) is implicated in a novel syndrome characterised by striatal thinning, congenital cataract and attention deficit hyperactivity disorder. Our study highlights potassium channels' role in ocular and neuronal genetics.
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Namik
authors: N
authors: Kaya
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Maysoon
authors: M
authors: Alsagob
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors: Maria Cristina
authors: MC
authors: D'Adamo
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Albandary
authors: A
authors: Al-Bakheet
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors: Sonia
authors: S
authors: Hasan
authors: College of Optometry, The Ohio State University, Columbus, Ohio, USA.
authors: Maria
authors: M
authors: Muccioli
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Faten B
authors: FB
authors: Almutairi
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Rawan
authors: R
authors: Almass
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Mazhor
authors: M
authors: Aldosary
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Dorota
authors: D
authors: Monies
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors: Osama M
authors: OM
authors: Mustafa
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Banan
authors: B
authors: Alyounes
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Rosan
authors: R
authors: Kenana
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Jawaher
authors: J
authors: Al-Zahrani
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Eva
authors: E
authors: Naim
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Faisal S
authors: FS
authors: Binhumaid
authors: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Alya
authors: A
authors: Qari
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Fatema
authors: F
authors: Almutairi
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Brian
authors: B
authors: Meyer
authors: College of Optometry, The Ohio State University, Columbus, Ohio, USA.
authors: Timothy F
authors: TF
authors: Plageman
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy.|Department of Physiology & Biochemistry Faculty of Medicine & Surgery, University of Malta, Msida, Malta.
authors: Mauro
authors: M
authors: Pessia
authors: Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Dilek
authors: D
authors: Colak
authors: College of Optometry, The Ohio State University, Columbus, Ohio, USA.|College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors: Mohammed
authors: M
authors: Al-Owain
keywords: Genetics; Linkage; Potassium Channel