A Novel Mutation of SLC26A4 Gene In an Iranian Family with Pendred Syndrome
Subgroup: Volume 3, Issue 2, Spring
Date: June 2005
Type: Original Article
Start Page: 104
End Page: 108
- K Kahrizi Genetic Research Center, University of Social Walfare and Rehabilitation Sciences, Tehran, Iran
- C Nishimura Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
- A Naghavi Genetic Research Center, University of Social Walfare and Rehabilitation Sciences, Tehran, Iran
- Y Riazalhosseini Genetic Research Center, University of Social Walfare and Rehabilitation Sciences, Tehran, Iran
- RJH Smith Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
- H Najmabadi Genetic Research Center, University of Social Walfare and Rehabilitation Sciences, Tehran, Iran
City, Province: Tehran,
In the diagnosis of Pendred syndrome, assessment of individuals by molecular analysis of the SLC26A4 gene is recommended. Here we report a novel mutation in the SLC26A4 gene as revealed by denaturing high performance liquid chromatography (DHPLC) and DNA sequencing of the entire coding region of the SLC26A4 gene in five members of an Iranian family affected with Pendred syndrome. This is the first report of the molecular investigation of Pendred syndrome in Iran and the first report of the R79X mutation.
Keywords: Pendred syndrome;congenital deafness;SLC26A4;R79X;mutation analysis;Iran Introduction
Pendred syndrome accounts for 1 to 10% of hereditary hearing loss in various world populations. It is the most common form of the syndromic hearing loss associated with thyroid dysfunction. 1
Although deficiency of the interscalar septum in the distal coils of the cochlea (Mondini deformity) has been found to be common,it is probably not a constant feature of Pendred syndrome.2 It has been stated that enlargement of the vestibular aqueduct, a radiologic marker, should be considered as the most likely presentation of Pendred syndrome.3
To assess deficiency in the bony interscalar septum of the cochlea (Mondini deformity) and to evaluate the (VA) Vestibular Aqueduct, high resolution computed tomography (CT) of temporal bones in the coronal and axial planes is performed. On the other hand, Magnetic Resonance Imaging (MRI) is used to examine enlargement of the endolymphatic sac and duct in association with a large VA.2,3
Patients suffering from undiagnosed Pendred syndrome often present with congenital hearing loss, but thyroid dysfunction could go undetected, might not arise until later in life or could even be compensated hypothyroidism. Indeed, thyroid dysfunction in Pendred syndrome varies and many patients remain euthyroid.4 For this reason, due to the nonspecific nature of the perchlorate discharge test,S the gold-standard investigation for Pendred syndrome, molecular analysis of the SLC26A4 gene in the assessment of individuals with severe to profound congenital hearing loss, is recommended.6
The SLC26A4 gene is located on chromosome 7q31 and contains 21 exons (Fig. 1 ).7 The encoded protein is pendrin, which is composed of 12 transmembrane domains.7,8 The SLC26A4 gene has a relatively restricted pattern of expression, with SLC26A4 mRNA detected only in the thyroid, inner ear, and kidney. An autosomal recessive locus for non-syndromic deafness designated DFNB4 also maps to 7q31, the same region as SLC26A4 gene. Mutations of the SLC26A4 gene are causative for both Pendred syndrome (MIM 274600) and DFNB4 (MIM 600791).9 The aim of this study was to determine the molecular cause ofPendred in the family studied.
Fig.1. The SLC26A4 gene location; the gene IS located on the long (q) arm of chromosome 7 at 7q31.1.
A 40-year~0Id male presented with'hereditary sensory neural hearing loss-with symptoms of hypothyroidism and goiter, at 38 years of age, detected by isotope scanning and ultrasonography. On physical examination, other organs abnormalities of the cardiovascular, central nervous system and of the skin were seen. There was no history of any other disorders related to hearing loss or usage of any medications resulting in hearing impairment. The patient had 5 siblings (Fig.2).There was a history of similar symptoms in two of his brothers (48 and 43 years old) and two sisters (45 and 21 years old). The affected individuals had congenital hearing loss and adult onset thyroid dysfunction. The age of onset for thyroid dysfunction varied in these affected siblings (Table. 1 ). We did not perform CT scan or MRI to rule out mondini deformity and V AE (Vestibular Aqueduct Enlargement). There was no information about thyroid function status prior to development of hypothyroidism.The parents' marriage was consanguineous (first cousins). The SLC26A4 gene was sequenced and we identified a novel mutation due to a nucleotide substitution (235C>T) (Fig.3.) in the third exon of SLC26A4 gene which results in a stop codon (R79X) (Fig.4)
Fig. 2. Pedigree of the family (wt: wild type)
Fig.3. Location of 235C>T mutation
Fig.4. Location of the R79X mutation in pendrin protein
Table 1. Clinical characteristics of study cases
|Clinical characteristics||Patient: oneIV:7||Patient: two IV:8||Patient: three IV:2||Patient: four IV:1||Patient: five IV:6|
|Age of cases||48||45||43||40||21|
|Age of onset of hypothyroidism||28||24||24||38||14|
|Age of onset of hearing impairment||Infancy||Infancy||Infancy||Infancy||Infancy|
|Severity of deafness||
|Uni-or bilateral deafness||Bilateral SNHL||Bilateral SNHL||Bilateral SNHL||Bilateral SNHL||Bilateral SNHL|
|Type of Hearing Loss||Non progressive||Non progressive||Non progressive||Non progressive||Non progressive|
|Imaging tests to rule out Mondini deafness and VAE||
|Not yet||Not yet||Not yet||Not yet|
This case report is an attempt to highlight the importance of considering Pendred syndrome in the differential diagnosis of those patients with congenital hearing impairment and especially mutation analysis in patients suspected of having Pendred syndrome. The molecular diagnosis of this family has led to the identification of a novel mutation, higher to unreported in other populations. Because population-specific differences are not uncornrnon, and the rate of consanguineous marriage in Iran is high, 38.6 for overall and
27.9 for first cousin marriages,1O it is important that the mutation spectrum of this gene to be investigated further in our popUlation. This patient had been initially diagnosed with congenital hearing loss but only upon detection of hypothyroidism and goiter at age 38, was a diagnosis of Pendred syndrome suspected. Pendred syndrome, the most cornrnon syndromic form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter) caused by mutations in the SLC26A4 gene. Mutations in this gene also cause non-syndromic deafness, DFNB4, as well as enlarged vestibular aqueduct syndrome (EVA). II Everett et al. found that the SLC26A gene encodes a 780-amino acid (86 kD) protein, an anion transporter known as Pendrin. Pendrin is closely related to a number of sulfate transporters and contains 12 transmembrane proteins.6
To date, 90 mutations have been found in the SLC26A4 gene, four of which (L236P, IVS8+ IG>A, T416P, and H723R) account for approximately 60% of the total Pendred genetic load.8
Functional studies by Scott et al. suggest that the observed phenotype correlates with the degree of residual function of the encoded protein, Pendrin. Thus, mutations that result in no residual transport function appear to be associated with the Pendred phenotype; minimal transport ability prevents thyroid dysfunction but not the (Sensorineural Hearing Loss) SNHL and temporal bone anomalies that characterize DFNB4.l2
The perchlorate discharge test, used in the diagnosis of Pendred syndrome, is nonspecific, and, in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown.5,6 Reardon et al. (1997) used the mapping of the Pendred syndrome gene to 7 q to identify pedigrees and assessed the prevalence of clinical parameters of the disease in affected individuals. Cosegregation between disease and the locus on 7q was found in 36 familial cases. Clinical and investigative findings were compared in 18 index cases versus 18 affected siblings. The overall prevalence of goiter was 73%. The prevalence was higher in index cases (94%) than in siblings (56%), many of whom had not previously been diagnosed with the condition. One perchlorate discharge test was falsenegative (2.9%). Radiologic malformations of the cochlea were identified in 86% of cases. Researchers in this study concluded that securing a diagnosis of Pendred syndrome may be difficult, especially in a single case. 13Over ninety different types of mutations have been reported in the SLC26A4 gene so far, most of which have been identified within western populations,8,ll though molecular investigation of Pendred syndrome has not been reported in our country.Our previous study regarding the epidemiology of GJB2 gene mutations among the autosomal recessive non-syndromic deaf (ARNSD) showed that prevalence of GJB2realted deafness is 16.7% in our population which is significantly different from reports published on Western populations. In addition, novel mutations have been found among these patients which have not been reported in other populations.14,l5 Further studies on the prevalence of SLC26A4 gene mutations in our population are required due to the fact that SLC26A4 gene mutations cause ARNSD without goiter as well. 11 We also suggest that mutation detection in the diagnosis of Pendred syndrome be applied to patients with the clinical indication of Pendred syndrome as a part of patient management.
This work was supported by the Iranian Deputy of Research and Technology, Minis try of Health & Medical Education Grant (P 6176).
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