that includes diabetes insipidus, diabetes mellitus, optic atrophy association between WFS1 mutations and diabetes mellitus and psychiatric illness. …
DFNA6/14/38 OMIM 600965 and Wolfram Syndrome OMIM 222300
DFNA6/14/38
Three overlapping DFNA loci have been mapped to 4p16 - DFNA6, DFNA14
and DFNA38 Lesperance 1995, Van Camp 1999, Young 2001 All are
associated with mutations in WFS1 OMIM 606201 Now referred to as the
DFNA6/14/38 locus, the phenotype is very distinctive and is characterized
by low frequency hearing loss that rises to normal in the high frequencies
Some persons report tinnitus, but not vertigo
Wolfram Syndrome
Mutations in WFS1 also cause Wolfram Syndrome OMIM 222300, a
recessively inherited disorder with a phenotype that includes diabetes
insipidus, diabetes mellitus, optic atrophy and deafness also known as
DIDMOAD syndrome Studies have shown an association between WFS1
mutations and diabetes mellitus and psychiatric illness
WFS1
The gene, WFS1, contains 8 exons; exons 2 -7 encode the 890 amino
acid protein Wolframin The majority of mutations causing low frequency
hearing loss are in the C-terminal portion of the protein; mutations
causing Wolfram Syndrome are spread throughout the gene Cryns et al,
2003 A listing of mutations identified in WFS1 can be found on the WFS1
Gene Mutation and
Polyporphism Database
http://wwwkhrimedumichedu/research/lesperance_lab/lfsnhlshtml
MORL screening methodology
Screening for WFS1 is performed by DHPLC and sequencing
Oligonucleotide primers have been designed to amplify each coding exon 2-
8 Amplified samples are resolved by DHPLC; abnormal elution profiles are
sequenced to identify the specific mutation Because exon 8 of WFS1 aa 289-
891 contains many non-disease causing polymorphisms, it is sequenced
directly using overlapping primer sets
DHPLC profile of WFS1, exon 5
Legend: Profile in brown contains a mutation; profile in purple is wild
type
Sensitivity
Sensitivity is greater than 98
Turn-around time
Turn around time is approximately 3 months
Cost: 500
Indications for screening
Families segregating autosomal dominant non-syndromic deafness with a low
frequency hearing loss and preserved high frequency hearing
GeneTests GeneReviews - Deafness and Hearing Loss
http://wwwgenetestsorg/servlet/access?dbgeneclinicssitegtid8888891ke
yTCu6wmKbIcXxKgryfcnyfwTRYtfilename/profiles/deafness-
overview/indexhtml
References
Lesperance, M M et al: A gene for autosomal dominant
nonsyndromic
hereditary hearing impairment maps to 4p163 Hum Molec Genet 4: 1967-
1972, 1995
PubMed ID : 8595423
Van Camp, G et al: A gene for autosomal dominant hearing impairment
DFNA14 maps to a region on chromosome 4p163 that does not overlap the
DFNA6 locus J Med Genet 36: 532-536, 1999
PubMed ID : 10424813
Young, T-L et al: Non-syndromic progressive hearing loss DFNA38 is
caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1
Hum Molec Genet 10: 2509-2514, 2001
PubMed ID : 11709538
Cryns, K et al: Mutational spectrum of the WFS1 gene in Wolfram
syndrome, nonsyndromic hearing impairment, diabetes mellitus, and
psychiatric disease Hum Mutat 22: 275-287, 2003
PubMed ID : 12955714
Lesperance, M M et al: Mutations in the Wolfram syndrome type 1 gene
WFS1 define a clinical entity of dominant low-frequency sensorineural
hearing loss Arch Otolaryngol Head Neck Surg 2003 Apr;1294:411-20
PubMed ID: 12707187
http://wwwncbinlmnihgov/entrez/queryfcgi?cmdRetrievedbpubmeddoptAb
stractlist_uids12707187query_hl11itoolpubmed_docsum
Smith, RJ: Clinical Application of Genetic Testing for Deafness Am J
Med Genet A 2004 Sep 15;1301:8-12
PubMed ID
15368487
http://wwwncbinlmnihgov/entrez/queryfcgi?cmdRetrievedbpubmeddoptAb
stractlist_uids15368487query_hl13itoolpubmed_docsum
Sivakumaran, Ta, Lesperance, MM 2003 WFS1 gene mutation and
polymorphism database
http://wwwkhrimedumichedu/research/lesperance_lab/lfsnhlshtml
