Christophe Pêcheux

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11–p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.

MEFV-Gene Analysis in Armenian Patients with Familial Mediterranean Fever: Diagnostic Value and Unfavorable Renal Prognosis of the M694V Homozygous Genotype—Genetic and Therapeutic Implications

Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis. Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P=.0002 and P=.006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families.

A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family.

OBJECTIVE To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor alpha (TNFalpha) receptor (TNFR1) in the pathogenesis of the disease. METHODS The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFalpha promoter by DNA sequencing. RESULTS Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Stills disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFalpha promoter. CONCLUSION TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.

Sequence analysis of the CCG polymorphic region adjacent to the CAG triplet repeat of the HD gene in normal and HD chromosomes.

The CAG expansion responsible for Huntingtons disease (HD) is followed by an adjacent polymorphic CCG repeat region which may interfere with a PCR based diagnosis. We have sequenced this region in 52 unrelated HD patients, from both normal and HD chromosomes. Fifty percent of the normal alleles were (CCG)7(CCT)2, 48% (CCG)10(CCT)2, and 2% (CCG)7(CCT)3. In contrast (CCG)7(CCT)2 was found in 85% of the HD alleles which represents significant linkage disequilibrium with the HD mutation.

Fibrinogen Act chain mutation (Arg554 Leu) associated with hereditary renal amyloidosis in a French family

A French family with hereditary renal amyloidosis (HRA) was studied. The disease presented in 7 of the 8 affected individuals with proteinuria or the nephrotic syndrome. The age of onset was in the fifth decade of life. There is currently no sign of extrarenal involvement in any affected individual. However, the nephropathy in this family is progressive and led to terminal renal failure in 4 patients. Immunohistochemistry studies of glomerular amyloid deposits suggested that the amyloid protein was the fibrinogen A alpha chain. Direct DNA sequencing revealed a G 4993 T transversion and subsequently Arg 554 Leu mutation in the fibrinogen A alpha chain. This is the first description of this fibrinogen A alpha chain mutation in Europe. This family is of French descent and cannot be related to the previously reported Peruvian/Mexican and African-American kindreds.