Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome

• Published in: Human mutation Vol. 14; no. 6; pp. 520 - 526
• Main Authors: López-Bigas, Núria, Rabionet, Raquel, de Cid, Rafael, Govea, Nancy, Gasparini, Paolo, Zelante, Leopoldo, Arbonés, Maria Lourdes, Estivill, Xavier
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.01.1999; Hindawi Limited
• Subjects: Amino Acid Sequence; Audiometry; Base Sequence; Carrier Proteins - genetics; Cochlea - abnormalities; deafness; DNA - genetics; Female; Genes, Recessive; Goiter - genetics; hearing loss; Hearing Loss, Sensorineural - congenital; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - physiopathology; Humans; Male; Membrane Transport Proteins; Mutation; PDS; Pedigree; Pendred syndrome; pendrin; Phenotype; RNA Splicing - genetics; Sulfate Transporters; Syndrome
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/(SICI)1098-1004(199912)14:6<520::AID-HUMU11>3.0.CO;2-K

Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has been mapped to chromosome 7q22‐q31, and encodes a chloride‐iodide transport protein. We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate–severe deafness). We identified a new splice‐site mutation affecting intron 4 of the PDS gene, at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A→G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS. Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation. Hum Mutat 14:520–526, 1999. © 1999 Wiley‐Liss, Inc.