Sheela Nampoothiri

Amrita Institute of Medical Sciences and Research Centre

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Katta M. Girisha

Manipal Academy of Higher Education

Dhanya Yesodharan

Amrita Institute of Medical Sciences and Research Centre

Anju Shukla

Kasturba Medical College, Manipal

Neerja Gupta

All India Institute of Medical Sciences

Shubha R. Phadke

Sanjay Gandhi Post Graduate Institute of Medical Sciences

Fransiska Malfait

Ghent University Hospital

Ratna Dua Puri

Sir Ganga Ram Hospital

Dhanya Lakshmi Narayanan

Hudson Institute of Medical Research

Jayesh Sheth

Centre For Human Genetics

Sofie Symoens

Ghent University

Cooperative Institutions

University of Washington

352

Washington Center

323

Inserm

258

University of Helsinki

242

Institute for Molecular Medicine Finland

187

National Center on Birth Defects and Developmental Disabilities

178

Harvard University

166

National Institute on Population Medical Genetics

166

University College London

142

Boston Children's Hospital

122

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Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

European Journal of Human Genetics (2022)

Tess Holling Sheela Nampoothiri Bedirhan Tarhan Pauline E. Schneeberger Kollencheri Puthenveettil Vinayan

Abstract The sodium (Na + ):multivitamin transporter (SMVT), encoded by SLC5A6 , belongs to the sodium:solute symporter family and is required for the Na + -dependent uptake of biotin (vitamin B7), pantothenic acid (vitamin B5), the vitamin-like substance α-lipoic acid, and iodide. Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. We identified the homozygous variant c.1285 A > G [p.(Ser429Gly)] in three affected siblings and a simplex patient and the maternally inherited c.280 C > T [p.(Arg94*)] variant and the paternally inherited c.485 A > G [p.(Tyr162Cys)] variant in the simplex patient of the third family. Both missense variants were predicted to affect function by in silico tools. 3D homology modeling of the human SMVT revealed 13 transmembrane helices (TMs) and Tyr162 and Ser429 to be located at the cytoplasmic facing region of TM4 and within TM11, respectively. The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity. Targeted therapeutic intervention yielded clinical improvement in four of the five patients. Early molecular diagnosis by exome sequencing is essential for timely replacement therapy in affected individuals.

10.1038/s41431-021-01033-2

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Citations (15)

Monosomy 1p36: Report of a cohort of 13 Asian Indian patients

American Journal of Medical Genetics Part A (2022)

Neerja Gupta Ravneet Kaur Shubha R. Phadke Pankaj Sharma Sheela Nampoothiri

Monosomy 1p36 is one of the common microdeletion syndromes with a recognizable facial phenotype. Failure to thrive, developmental delay, congenital heart disease, and other abnormalities are common in these patients. This is the first study on Asian Indian patients with monosomy 1p36, documenting the phenotypic characteristics of 13 patients, indicating phenotypic similarities in a diverse population and broadening the clinical spectrum.

Monosomy

Failure to Thrive

Clinical phenotype

10.1002/ajmg.a.62630

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Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy

The American Journal of Human Genetics (2013)

Karina Tuz Ruxandra Bachmann‐Gagescu Diana R. O’Day Kiet Hua Christine R. Isabella

Ciliopathy

Joubert syndrome

Ciliogenesis

Ciliopathies

Haploinsufficiency

Nephronophthisis

Morpholino

Intraflagellar Transport

10.1016/j.ajhg.2013.11.019

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Citations (108)

Issue Information

Human Mutation (2018)

Johan T. den Dunnen Samya Chakravorty Madhuri Hegde Patrice Bourgeois Clothilde Estève

10.1002/humu.23327

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Citations (0)

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation

Genetics in Medicine (2016)

Karim Kouz Christina Lißewski Stephanie Spranger Diana Mitter Angelika Rieß

Noonan Syndrome

10.1038/gim.2016.32

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Citations (91)

Congenital myotonic dystrophy with asymptomatic mother.

PubMed (2011)

Khushboo Anand Virupaxappa Biradar Jalesh N. Panicker Sheela Nampoothiri

Source

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Citations (2)

Arterial tortuosity syndrome: 37 new families and literature review

Aude Beyens Juliette Albuisson Tiffany Lepard N Canham JM Chopin

Tortuosity

Source

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Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

Human Molecular Genetics (2021)

Elena Botta Arjan F. Theil Anja Raams Giuseppina Caligiuri Sarah Giachetti

Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulfur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) forms exhibits in addition to progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD. These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasize this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription redefines TTD as a syndrome in which proteins involved in gene expression are unstable.

Transcription

Amino Acyl-tRNA Synthetases

10.1093/hmg/ddab123

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Citations (28)

Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Genetics in Medicine (2020)

Li Xin Zhang Gabrielle Lemire Claudia Gonzaga‐Jauregui Sirinart Molidperee Carolina Galaz-Montoya

Polydactyly

Expressivity

Broad spectrum

10.1038/s41436-020-0811-8