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Transcript
Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene Teresa Esposito1^, Rod A Lea2^, Bridget H Maher2, Dianne Moses2, Hannah C Cox2, Sara Magliocca1, Andrea Angius3, Dale R Nyholt4, Thomas Titus5, Troy Kay5, Nicholas A Gray6, Maria P Rastaldi7, Alan Parnham5, Fernando Gianfrancesco1+, Lyn R Griffiths2+* ^ Joint First Authors + Joint Senior Authors 1 Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy. 2 Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Queensland, 4222, Australia. 3 Institute of Genetic and Biomedical Research, National Research Council of Italy, Cagliari, Italy. 4 Queensland Institute of Medical Research, Herston Road, Herston, Brisbane, 4006, Australia 5 Renal Department, Gold Coast Hospital, Queensland, Australia 6 Renal Services, Nambour Hospital, Nambour, Queensland, Australia 7 Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milano, Italy Corresponding author: * Professor Lyn Griffiths, Genomics Research Centre, Griffith Health Institute, Griffith University, Queensland 4222, Australia.; Phone +61 7 5552 8664, fax +61 7 5552 9081, email: [email protected] Supplementary Table. 1 Summary of the molecular genetics of FSGS and progressive heart block Disorder Inheritance Locus Gene Protein FSGS1 FSGS2 Aut. Dom Aut. Dom 19q13 11q21-q22 ACTN4 TRPC6 -actinin 4 Transient recept. pot. cat. chan. 6 FSGS3 Aut. Rec 6p12 CD2AP CD2 – associated protein FSGS4 Aut. Dom 22q12 MYH9 Myosin, heavy chain 9 NPHS1 Aut. Rec 19q13.1 NPHS1 Nephrin NPHS2 Aut. Rec 1q25-q31 NPHS2 Podocin NPHS3 Aut. Rec 10q23.32-q24.1 PLCE1 Phospholipase C Epsilon FSGS Aut. Dom 14q32.33 INF2 Formin FSGS Aut. Rec 15q21 MYO1E Myosin 1E PFHB1A Aut. Dom 3p21 SCN5A Sodium Channel, voltage-gated, type V PFHB1B Aut. Dom 19q13.2-q13.3 TRPM4 Transient receptor potential cation channel PFHB2 Aut. Dom 1q32.2-q32.3 Unknown Supplementary Table 2. Table of pathologies in the pedigree Pathology Individuals FSGS Premature death in generations I,II,III – family history suggests renal failure ID1, ID8, ID12 FSGS not confirmed by renal biopsy* ID14, ID16, ID50, ID62 FSGS confirmed by renal biopsy ID69, ID75, ID85, D136 Kidney Transplant ID62, ID69, ID105 Cardiac Conduction Defects Cardiac conduction defects ID14, ID16, ID50, ID69, ID75, ID85 Pacemaker ID14, ID50, ID69, ID75, ID85 Other Renal Tumours ID30, ID34, ID39, ID100 ID34, ID47, ID55, ID59, ID80 ID82, Pre-eclampsia and hypertension ID84, ID88, ID139, ID142 Asymptomatic proteinuria (carriers) ID34, ID47, ID55, ID78 * A histological diagnosis of the renal pathology is unavailable for these four affected males as they died prior to the development of renal biopsy as a routine clinical investigation in the regions they were residing. Supplementary Table. 3 Summary of the molecular genetics analysis of candidate genes located in linkage interval. Gene Protein Inheritance Disorder Candidate gene status GLA Disorder CLDN2 Galactosidase, ALPHA Claudin 2 Fabry Disease No mutations No mutations COL4A5 Collagen, type IV, ALPHA-5 Alport Syndrome No mutations TRPC5 Transient Receptor Potential Cation No mutations AMOT Channel, Subfamily C, Member 5 Angiomotin No mutations These five genes were analysed by direct sequencing of all exons including exon-intron boundary. Primers sequences are available on request. Supplementary Figure 1 The complete 6-generational Australian FSGS pedigree. Supplementary Figure 2 Genomic map of the candidate interval showing all genes housing this region. Underlined are indicated the candidate genes analysed by direct sequencing. Supplementary Figure 3: Exome sequencing analysis. A, coverage of part of the COL4A5 gene located in the linkage interval. B sequence of the exon 12 of the COL4A5 gene containing the codon 222 that was mutated in a patient with glomerulopathy. Supplementary Figure 4 SIFT prediction of the R113W mutation in NXF5 gene. From amino acid 101 to 121 are reported and the position 113 is indicated with a rectangle. At left are indicated the deleterious changes and at right are indicated the tolerated changes.
