Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene.

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. Mutations in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4, 5-biphosphate (PtdIns[4,5]P2) 5-phosphatase. We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein. A missense mutation, R483G, was located in the highly conserved PtdIns(4,5)P2 5-phosphatase domain. Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11-15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This observation has direct implications for genetic counseling of Lowe syndrome families

SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population