Edition of 06 February 2007

Kostmann disease is a severe congenital neutropenia characterised by a recessive autosomal transmission. A German team has identified a Hax1 mutation in 3 Kurdish families. The study was thereafter extended to 3 other families in addition to the 3 patients initially described by Kostmann. Hax1 is a mitochondrial protein expressed in a curiously ubiquitous manner.

In this study, the researchers have systematically sequenced the CFL2 gene, encoding the Cofilin-2 protein known for its role in the dynamics of the actin filaments. The analysis of 113 patients with nemaline myopathy has made it possible to identify a brother and a sister carrying a homozygote mutation.

Osteogenesis imperfecta constitutes a group of hereditary disorders responsible, in different degrees, for the fragility of the skeleton. Most frequently, gene mutations encoding type I collagen are at the origin of dominant autosomal forms of the disease. However, forms involving recessive autosomal transmission have already been described. CRTAP, a protein required for the post-translational (propyl-3-hydroxylation) modification of type I collagen, is a potential candidate. Barnes et al. have sequenced the gene encoding CRTAP and identified recessive mutations in 3 children with osteogenesis imperfecta.
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Two independent studies published in Nature Genetics reports on the identification of mutations in the SOS1 gene in patients affected by Noonan syndrome. These patients of short stature have a characteristic facial dysmorphia and congenital cardiac anomalies. Former studies suggest that a deregulation of the RAS-MAPK pathway may be at the origin of this disease’s development. Sequence analysis of genes whose products act before the RAS and ERK proteins has made it possible to identify different mutations of the SOS1 gene, encoding a RAS guanine exchange factor. All the mutations identified to date in the Noonan syndrome currently increase the activation of the RAS-MAPK pathway.

The Li-Fraumeni syndrome is a cancer predisposition which is transmitted in an autosomal dominant manner. Mutations in the p53 gene, encoding a tumour suppressor, are the main cause of this syndrome. In this study, Dutch researchers have shown that the polymorphism of the MDM2gene whose product is a negative p53 regulator, is associated with the precocious development of tumours in patients carrying a p53 mutation.

Angelman syndrome is a neurodevelopmental disorder caused by a failure of expression of the maternal copy of the unprinted UBE3A gene. In this article, Boyes et al. report on a new method based on a semi-quantitative amplification by PCR making it possible to detect the micro-deletions of the UBE3A gene.

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Neurofibromatosis type I is a dominant autosomal disorder characterised by café-au-lait spots and cutaneous neurofibromas. The mutations of the NF1 gene, encoding Neurofibromin, caused the disease. No correlation between the genotype and the phenotype of the patients has been observed to date in the case of small mutations. In this study, 21 unrelated patients not affected by cutaneous or plexiform neurofibroma all carry the same deletion of 3 pairs of bases. This deletion bears the loss of methionin in a well conserved region of the protein. The functional explication of this correlation between the genotype and phenotype is not clarified.