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In the course of positional cloning of the Congenital Dyserythropoietic Anemia type I (CDAI) [MIM 224120] gene on 15q15.1-15.3, we examined a family of French origin, in which the propositus suffered from asthenoteratozoospermia and nonsyndromic deafness in addition to CDAI. Two of his brothers had a similar phenotype. All three siblings were homozygous carriers of the CDA1 mutation as well as of a distally located ∼70 kb deletion of the proximal copy of a 106 kb tandem repeat on chromosome 15q15. These repeats encode four genes whose distal copies may be considered pseudogenes. Lack of functional stereocilin and CATSPER2 (a voltage-gate cation channel expressed specifically in spermatozoa) may explain the observed deafness and male infertility phenotypes. To the best of our knowledge, the involvement of CATSPER2 in asthenoteratozoospermia is the first description of a human autosomal gene defect associated with nonsyndromic male infertility. [ABSTRACT FROM AUTHOR]

Introduction: A total of 25% of patients presenting with Diamond-Blackfan anemia (DBA) carry mutations in the rps19 gene, which encodes protein RPS19 of the small ribosomal subunit. The other DBA cases carry mutations in other, unknown gene(s). Materials and methods: We searched mutations in 48 DBA families or isolated patients based on PCR of exons of the rps19 gene and automatic sequencing. We also studied three novel intronic polymorphisms in 85 persons (most of the patients and their relatives, when the latter could be investigated). Results: We identified 10 new mutations within the rps19 gene. We found no obvious correlation between the clinical expression and the nature of the mutation. Besides, we found three polymorphisms within the rps19 gene. Polymorphisms a, b and c were (i) a one-base insertion (+ c at position + 79) in intron 2, (ii) the g←c substitution at position + 89 also in intron 2 and (iii) the g←a substitution at position + 14 in intron 4. Inheritance studies showed that the polymorphisms were transmitted en bloc, thus defining the --- haplotypes (changes absent) and the + + + haplotypes (changes present). The percentages of each haplotype were about 50% in families and isolated persons with DBA, as well as in controls. Conclusion: For the 10 novel mutations found in the rps19 gene, there were no obvious genotype-phenotype correlations. The transmission of the polymorphisms was en bloc and the studies did not suggest any clinical correlates at this stage. [ABSTRACT FROM AUTHOR]

Primitive neuroectodermal tumors (PNET)–medulloblastomas account for approximately 20% of all brain tumors in children. Ataxia-telangiectasia is an autosomal recessive neurological disorder with predisposition to cancer. The most common neoplasms are lymphoid malignancies and solid tumors, including central nervous system tumors, astrocytomas, and medulloblastomas. To investigate the potential role of the ATM gene in the pathogenesis of medulloblastoma, 13 tumors were screened for ATM mutations and 9 for loss of heterozygosity (LOH) of the ATM locus and flanking regions. In none of the tumors were mutations identified. In five of them, the well-known polymorphisms D1853N and F858L were identified and in all 22 tumors, the wild-type allele was preserved. The frequency of the polymorphisms was similar to that reported in our and other normal populations. The LOH of the 11q region (including the ATM gene), detected in 25% of informative cases, is consistent with the molecular and cytogenetic reports of deletion of chromosome 11 in 13%–41% of medulloblastomas. These results indicate that mutations in the ATM gene do not play a role in the pathogenesis of medulloblastoma in children. The LOH in the 11q region may suggest hidden unidentified tumor suppressor genes that may be involved in the malignant transformation. [Copyright &y& Elsevier]