C.W.R.J. Cremers

SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma

Tapping the Mitochondrial Proteome Mitochondria produce the energy that cells need to survive, function, and divide. A growing list of human disorders has been traced to defects in mitochondrial function. About 300 mammalian mitochondrial proteins are functionally uncharacterized, and Hao et al. (p. 1139, published online 23 July) reasoned that the most highly conserved proteins within this group might provide insights into human disease. A combination of bioinformatics, yeast genetics, biochemistry, and human genetics was used to show that a previously uncharacterized mitochondrial protein (Sdh5) is required for the activity of respiratory complex II. Inactivating mutations in the human gene encoding SDH5 were found in individuals with hereditary paraganglioma, a rare neuroendocrine tumor. Thus, analysis of a mitochondrial protein in yeast has revealed a human tumor susceptibility gene. Analysis of a yeast mitochondrial protein reveals a human tumor susceptibility gene. Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.

GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor β superfamily of signalling proteins (TGFβ-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFβ-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13)

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma

BACKGROUND Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype. METHODS We undertook a multicentre study in Spain and The Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype. FINDINGS We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred. INTERPRETATION SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes. FUNDING Dutch Cancer Society, European Union 6th Framework Program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer.

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

Consensus statements on the BAHA system: where do we stand at present?

After more than 25 years of clinical experience, the BAHA (bone-anchored hearing aid) system is a well-established treatment for hearing-impaired patients with conductive or mixed hearing loss. Owing to its success, the use of the BAHA system has spread and the indications for application have gradually become broader. New indications, as well as clinical applications, were discussed during scientific roundtable meetings in 2004 by experts in the field, and the outcomes of these discussions are presented in the form of statements. The issues that were discussed concerned BAHA surgery, the fitting range of the BAHA system, the BAHA system compared to conventional devices, bilateral application, the BAHA system in children, the BAHA system in patients with single-sided deafness, and, finally, the BAHA system in patients with unilateral conductive hearing loss.

Mutations in different components of FGF signaling in LADD syndrome.

Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by lacrimal duct aplasia, malformed ears and deafness, small teeth and digital anomalies. We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand. These findings increase the spectrum of anomalies associated with abnormal FGF signaling.

Linkage of Autosomal Dominant Hearing Loss to the Short Arm of Chromosome 1 in Two Families

BACKGROUND At least half of the cases of profound deafness of early onset are caused by genetic factors, but few of the genetic defects have been identified. This is particularly true of the most common hereditary forms of deafness, which occur in the absence of any associated syndrome. METHODS We studied a large Indonesian family in which hearing loss was inherited in an autosomal dominant pattern. The hearing loss first affects the high frequencies during the teens or 20s and becomes profound within 10 years. To locate the responsible gene, we performed genetic-linkage analysis, using microsatellite markers distributed over the entire genome. We then performed linkage analyses in an American family and a Dutch family with similar patterns of hereditary hearing loss. RESULTS In the extended Indonesian family, a gene linked to deafness mapped to chromosome 1p, with a multipoint lod score of more than 7. In the American family, deafness was linked to the same locus on chromosome 1p, with a multipoint lod score of more than 5. In the Dutch family, however, this locus was ruled out. The flanking markers D1S255 and D1S211 defined a region of 6 cM on chromosome 1p that is likely to contain the gene associated with deafness in the first two families. CONCLUSIONS In some families with early-onset autosomal dominant hearing loss, the responsible gene is on chromosome 1p.

Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity

Autosomal, dominantly inherited, non-chromaffin paragangliomas are tumors of the head and neck region occurring with a frequency of 1∶30 000. Genomic imprinting probably influences the expression of the disorder, because tumor development is limited to individuals who have inherited the trait from their father. By linkage analysis and haplotyping of a single large family in which the pattern of inheritance is consistent with genomic imprinting, we have mapped the gene to a 5 cM region of chromosome 11q13.1 between D11S956 and PYGM. A maximum lod score of 7.62 at Θ = 0.0 was obtained for D11S480. This interval does not overlap with a recently assigned locus for glomus tumors in other families: 11q22.3-q23.3. Furthermore, analysis of a second family showing the imprinting phenomenon resulted in the exclusion of the 5 cM area as the location of the disease gene, whereas an indication for linkage was obtained (Z = +2.65) with markers from the distal locus. These observations argue for the presence of two distinct imprinted genes for glomus tumors on 11q. A model for tumor initiation and progression is presented based on all available information.