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.
Satre
V
V
Laboratoire de Biochimie de l'ADN, CHU Grenoble, 4 Laboratoire BECP- EA 2019 UJF, DBMS, CEA, Grenoble, France.
Monnier
N
N
Berthoin
F
F
Ayuso
C
C
Joannard
A
A
Jouk
P S
PS
Lopez-Pajares
I
I
Megabarne
A
A
Philippe
H J
HJ
Plauchu
H
H
Torres
M L
ML
Lunardi
J
J
D000595:Amino Acid Sequence; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D011506:Proteins; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human