Sara Gil-Perotín1,2, Teresa Jaijo3,4,5, Andrés G Verdú6, Pilar Rubio6, Miguel Mazón7, Raquel Gasqué-Rubio8, Samuel Díaz9. 1. Neurology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain. sara.garcia@uv.es. 2. Neuroimmunology Unit, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain. sara.garcia@uv.es. 3. Genetic Unit, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain. 4. Molecular, Cellular and Genomics Biomedicine Research Group, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain. 5. CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. 6. Neurophysiology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain. 7. Radiology Department, Hospital Arnau de Vilanova, C/San Clemente, 12, 46025, Valencia, Spain. 8. Neuroimmunology Unit, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain. 9. Neurology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain.
Abstract
BACKGROUND: Recessive mutations in the SLC4A4 gene cause a syndrome characterised by proximal renal tubular acidosis (pRTA), mental retardation, dental and ocular abnormalities, and hemiplegic migraine. Rare cases involving the development of epilepsy or its severe complication-status epilepticus-have been described. METHODS: The clinical and genetic status of four affected members in a Spanish family was studied. The SLC4A4 gene mutation was detected with a next-generation sequencing (NGS) panel in the proband, and Sanger confirmed the putative mutations in affected relatives. In silico analysis was performed to elucidate the putative effect of mutation on the splicing process. RESULTS: A novel mutation, c.2562+2T>G, was identified in the homozygous state in all diseased members of the family. This mutation affected a canonical splice site and is predicted to abolish the wild-type donor site, which predicts a premature truncated NBCe1 protein with cotransport activity. The resulting protein lacks the 190 amino acids of the carboxyl-terminus, and the effect is likely to be a loss of function. All patients suffered from severe pRTA and ocular abnormalities, and the adults also suffered from neurological complications, such as hemiplegic migraine and/or epilepsy. Two developed life-threatening status epilepticus, although they fully recovered and remained free of seizures with valproate. CONCLUSION: These results expand the clinical and mutational spectra of SLC4A4-related disease and have implications for understanding the potential role of NBCe1 in the pathophysiologic processes of hemiplegic migraine and epilepsy/status epilepticus associated with the mutation.
BACKGROUND: Recessive mutations in the SLC4A4 gene cause a syndrome characterised by proximal renal tubular acidosis (pRTA), mental retardation, dental and ocular abnormalities, and hemiplegic migraine. Rare cases involving the development of epilepsy or its severe complication-status epilepticus-have been described. METHODS: The clinical and genetic status of four affected members in a Spanish family was studied. The SLC4A4 gene mutation was detected with a next-generation sequencing (NGS) panel in the proband, and Sanger confirmed the putative mutations in affected relatives. In silico analysis was performed to elucidate the putative effect of mutation on the splicing process. RESULTS: A novel mutation, c.2562+2T>G, was identified in the homozygous state in all diseased members of the family. This mutation affected a canonical splice site and is predicted to abolish the wild-type donor site, which predicts a premature truncated NBCe1 protein with cotransport activity. The resulting protein lacks the 190 amino acids of the carboxyl-terminus, and the effect is likely to be a loss of function. All patients suffered from severe pRTA and ocular abnormalities, and the adults also suffered from neurological complications, such as hemiplegic migraine and/or epilepsy. Two developed life-threatening status epilepticus, although they fully recovered and remained free of seizures with valproate. CONCLUSION: These results expand the clinical and mutational spectra of SLC4A4-related disease and have implications for understanding the potential role of NBCe1 in the pathophysiologic processes of hemiplegic migraine and epilepsy/status epilepticus associated with the mutation.
Entities:
Keywords:
NBCe1; Paroxysmal movement disorders; Roma ancestry; Seizures; Status epilepticus
Authors: T Igarashi; J Inatomi; T Sekine; S H Cha; Y Kanai; M Kunimi; K Tsukamoto; H Satoh; M Shimadzu; F Tozawa; T Mori; M Shiobara; G Seki; H Endou Journal: Nat Genet Date: 1999-11 Impact factor: 38.330
Authors: Masashi Suzuki; Maria Helena Vaisbich; Hideomi Yamada; Shoko Horita; Yuehong Li; Takashi Sekine; Nobuo Moriyama; Takashi Igarashi; Yoko Endo; Thaís P Cardoso; Luis Carlos F de Sá; Vera H Koch; George Seki; Toshiro Fujita Journal: Pflugers Arch Date: 2007-07-28 Impact factor: 3.657