1. TULIP1 (RALGAPA1) haploinsufficiency with brain development delay
- Author
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Toru Higashinakagawa, Mayu Ohtsu, Yu-ichi Goto, Hirokazu Oguni, Toshiyuki Yamamoto, Kousaku Ohno, Eiji Nakagawa, Keiko Shimojima, Yuta Komoike, Jun Tohyama, Sonoko Takahashi, Makiko Osawa, and Marco T. Páez
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Male ,Candidate gene ,Developmental delay ,Developmental Disabilities ,Molecular Sequence Data ,Mutation, Missense ,Nerve Tissue Proteins ,medicine.disease_cause ,Intellectual Disability ,medicine ,Genetics ,Missense mutation ,Animals ,Humans ,Amino Acid Sequence ,Child ,Codon ,Gene ,Zebrafish ,Conserved Sequence ,Chromosomes, Human, Pair 14 ,Gene knockdown ,Mutation ,TULIP1 (RALGAPA1) ,Epilepsy ,biology ,Sequence Homology, Amino Acid ,GTPase-Activating Proteins ,Brain ,Zebrafish Proteins ,biology.organism_classification ,Phenotype ,Pedigree ,Chromosomal deletion ,Gene Knockdown Techniques ,Muscle Hypotonia ,Epilepsy, Generalized ,Female ,Chromosome Deletion ,Haploinsufficiency ,Sequence Alignment ,Human - Abstract
A novel microdeletion of 14q13.1q13.3 was identified in a patient with developmental delay and intractable epilepsy. The 2.2-Mb deletion included 15 genes, of which TULIP1 (approved gene symbol: RALGAPA1)was the only gene highly expressed in the brain. Western blotting revealed reduced amount of TULIP1 in cell lysates derived from immortalized lymphocytes of the patient, suggesting the association between TULIP1 haploinsufficiency and the patient's phenotype, then 140 patients were screened for TULIP1 mutations and four missense mutations were identified. Although all four missense mutations were common with parents, reduced TULIP1 was observed in the cell lysates with a P297T mutation identified in a conserved region among species. A full-length homolog of human TULIP1 was identified in zebrafish with 72% identity to human. Tulip1 was highly expressed in zebrafish brain, and knockdown of which resulted in brain developmental delay. Therefore, we suggest that TULIP1 is a candidate gene for developmental delay.
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