title: Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient.
abstract: Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs*12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs*12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity.
authors.affiliation: School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India.
authors.forename: Paramasivam
authors.initials: P
authors.lastname: Manimaran
authors.affiliation: Departments of Medicine, Physiology/Biophysics, University of California, Irvine, CA; Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
authors.forename: Veedamali S
authors.initials: VS
authors.lastname: Subramanian
authors.affiliation: School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India.
authors.forename: Sellamuthu
authors.initials: S
authors.lastname: Karthi
authors.affiliation: School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Gandhimathi
authors.affiliation: School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Varalakshmi
authors.affiliation: Kanchi Kamakoti CHILDS Trust Hospital, Nungambakkam, Chennai 600 034, India.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Ganesh
authors.affiliation: Department of Cardiothoracic Surgery, Madurai Medical College, Madurai 625 020, India.
authors.forename: Andiappan
authors.initials: A
authors.lastname: Rathinavel
authors.affiliation: Departments of Medicine, Physiology/Biophysics, University of California, Irvine, CA; Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Said
authors.affiliation: School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India. Electronic address: rbashokkumar@yahoo.com.
authors.forename: Balasubramaniem
authors.initials: B
authors.lastname: Ashokkumar
mesh_terms: D000749:Anemia, Megaloblastic / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D003920:Diabetes Mellitus / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007194:India; D026901:Membrane Transport Proteins / Q000235:genetics*; D013832:Thiamine Deficiency / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human
keywords: Retinitis pigmentosa; SLC19A2; TRMA; hTHTR-1