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We studied 325 thalassemia intermedia patients from Iran, India, Pakistan, Thailand, Mauritius and Cyprus to examine factors which influence the phenotype. The β-thalassemia (thal) mutations were determined for 219 β-thal/β-thal and 106 β-thal/Hb E [β26(B8)Glu→Lys, GAG→AAG] thalassemia intermedia patients. Thirty-one different mutations were identified, and their combination gave rise to more than 44 different genotypes, of which 14 (31.8%) had the β0/β0, 21 (47.7%) the β0/β+ and nine (20.5%) the β+/β+ types. Thus, the β+-thal mutations were present in 68.2% of patients. α-Thalassemia mutations were present in frequencies higher than in the general population of all ethnic groups studied, as 45% of the patients carried α-thal mutations. Correlation of α-thal mutations with β-globin mutations showed that the α-thal mutations were mainly co-inherited with the β+-thal mutations. The XmnI Gγ polymorphic site at -158 (C→T) was positive (T) in nine (8.8%) of 102 patients of the β+/β+ genotype, and the percentage of both XmnI Gγ polymorphism [+/-] (T/C) and [+/+] (T/T) genotypes increased to 42.9 and 87.3, respectively, in the β0/β+ and β0/β0 patients. This polymorphism was found in the majority of β+-thal/Hb E compound heterozygote patients (88.6%), and β0-thal/Hb E patients (84.8%), suggesting that it could be linked to the Hb E chromosome. Therefore, the XmnI Gγ polymorphism at -158 (C→T) was associated with β0-thal mutations as well as the Hb E chromosome. The present study demonstrates that in cases of thalassemia intermedia with β+ mutations, the common ameliorating factor is the presence of α-thal mutations, while in cases with β0 mutations, the common ameliorating factor is the presence of the XmnI Gγ polymorphism at -158 (C→T). [ABSTRACT FROM AUTHOR]

A gene causing autosomal-recessive, nonsyndromic hearing loss, DFNB39, was previously mapped to an 18 Mb interval on chromosome 7q11.22-q21.12. We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and refined the obligate interval to 1.2 Mb. The coding regions of all genes in this interval were sequenced, and no missense, nonsense, or frameshift mutations were found. We sequenced the noncoding sequences of genes, as well as noncoding genes, and found three mutations clustered in intron 4 and exon 5 in the hepatocyte growth factor gene (HGF). Two intron 4 deletions occur in a highly conserved sequence that is part of the 3' untranslated region of a previously undescribed short isoform of HGF. The third mutation is a silent substitution, and we demonstrate that it affects splicing in vitro. HGF is involved in a wide variety of signaling pathways in many different tissues, yet these putative regulatory mutations cause a surprisingly specific phenotype, which is nonsydromic hearing loss. Two mouse models of Hgf dysregulation, one in which an Hgf transgene is ubiquitously overexpressed and the other a conditional knockout that deletes Hgf from a limited number of tissues, including the cochlea, result in deafness. Overexpression of HGF is associated with progressive degeneration of outer hair cells in the cochlea, whereas cochlear deletion of Hgf is associated with more general dysplasia.

In seven families, six different mutant alleles of TRIOBP on chromosome 22q13 cosegregate with autosomal recessive nonsyndromic deafness. These alleles include four nonsense (Q297X, R788X, R1068X, and R1117X) and two frameshift (D1069fsX1082 and R1078fsX1083) mutations, all located in exon 6 of TRIOBP. There are several alternative splice isoforms of this gene, the longest of which, TRIOBP-6, comprises 23 exons. The linkage interval for the deafness segregating in these families includes DFNB28. Genetic heterogeneity at this locus is suggested by three additional families that show significant evidence of linkage of deafness to markers on chromosome 22q13 but that apparently have no mutations in the TRIOBP gene.