TOPIC: P endrin gene mutation induces poor organification, iodine retention & high deiodinase activity
Title: Pendred syndrome in two Galician Families: insights into clinical phenotypes through cellular, genetic and molecular studies.
Authors: Palos F, Garcia-Rendueles ME, Araujo-Vilar D, Obregon MJ, Calvo RM et al.
Reference: Journal of Clinical Endocrinology & Metabolism 93: 267-277, 2008
Pendred Syndrome is an autosomal recessive disorder characterized by congenital sensorineural hearing loss (enlarged acqueduct, cochlear defects) and variable incidence of goiter with or without hypothyroidism. Mutations in the SLC26A4 (soluble carrier family 26, member 4) gene affects Pendrin, a transmembrane protein expressed in the thyroid apical membrane, inner ear and elsewhere. Pendrin is involved in iodide transport (as well as in chloride, formate and nitrate transport).
Two families from Galicia (Spain) were studied. In family A, the proposita had a large goiter and low serum T4 (but normal serum TSH and Free T3). In Family B, affected members showed deafness but not goiter. The objective was to identify the mutations causing Pendred syndrome as well as genetic and cellular mechanisms underlying the phenotypes A and B.
Pendrin gene (SLC26A4) gene analysis, deiodinase activity in the goitrous tissue, a primary goiter thyrocyte culture and comparison with culture of normal human thyrolytes (western blotting, cofocal microscopy and iodine uptake kinetics).
Proposita A (43 year old deaf woman) had a large multinodular goiter, with normal serum TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. She was compound heterozygous for a frameshift mutation at exon 3 (c.279 delT) and a C.578C →T at exon 5. This late mutation results in replacement of c.Thr193Ile. In family B, the propositus (a 26 year old deaf male) bore c.279 delT and a novel mutation c.416-1G →A but no goiter. Thyrocyte cell culture showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention.
Lack of apical pendrin immunoreactivity was due not only to functional impairment of pendrin but also to defective membrane targeting. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter (avoiding clinical hypothyroidism). Lack of goiter in subjects homozygous for c.416-1G → A was due to incomplete penetrance (some wild type pendrin was generated). Intracellular iodine retention and consequent accumulation confirms the importance of pendrin as an iodide transporter.
In this remarkable article, the authors describe two families with Pendred syndrome from Galicia (Spain). The founder mutation c.279delT (exon 3) causes a frameshift that introduces a stop codon 3 amino acids downstream. The other mutation c.578C → T (exon 5) results in the replacement of a normal threonine with isoleucine at codon 193. The c.416-1G → A located at the acceptor splice site of intron 4 (a novel mutation) replaces a G with an A and had an incomplete penetrance, as some wild type pendrin is translated.
Functional studies were conducted in goitrous tissues and normal thyroid specimens. Deiodinase activity was higher in goitrous tissue of patient A, as compared to normal thyroid tissue. MCT8 mRNA expression was also high in this goiter. Although NIS was normally located in the plasma membrane, pendrin was retained outside the Golgi (retained intracellularly). Thus, a high iodine uptake with low iodine efflux led to iodine retention within goitrous follicular cells. Increased D1 & D2 expression and activity were considered to be an adaptative response in order to maintain normal T3 supply, at the expense of T4: hence, the normal serum TSH obseerved in patient A. Moreover, urinary iodine excretion was normal (102 'g/L) indicating a normal nutritional iodine intake. The perchlorate discharge test confirmed the increased intracellular iodine pool with a positive discharge.
Distinct phenotypic clinical appearances are common in large families with Pendred syndrome with or without goiter, with isolated deafness or deafness combined with goiter. The c.279 delT is a founder mutation in Galicia.
In summary, this rather informative and complete study contributes much to our understanding of the patho-physiology of the Pendred syndrome.
Summary and commentary prepared by Geraldo Medeiros-Neto (Related to Chapters 2 & 16b of TDM)