A Premature Termination Mutation in a Patient with Lowe Syndrome without Congenital Cataracts: Dropping the “O” in OCRL

Abstract

Background:

The oculocerebrorenal syndrome of Lowe is an X-linked recessive disorder characterized by the triad of congenital cataracts, mental retardation and a renal proximal tubulopathy. Although severity of phenotype might vary, congenital cataracts are part of the definition of this rare disorder.

Patient and Methods:

We report a 13-year-old patient with the typical cerebrorenal phenotype of Lowe syndrome, that had remained undiagnosed due to absence of any ocular involvement. OCRL gene analysis was carried.

Results:

DNA analysis revealed a c.C760T (p.Gln199X) nonsense mutation in exon 8 expected to cause complete disruption of OCRL function. After sequencing the parents of the index patient and his maternal grandparents, this mutation turned out to be de novo in the mother. Furthermore, a silent variant (p.Arg35=) was identified in exon 2, that could also be identified in the mother and her 3 sisters, but not in the grandparents assuming germ cell mosaicism in either of the grandparents. RNA analysis from the patient’s lymphocytes revealed presence of full-length OCRL transcripts. Western blotting from lymphocyte samples failed to detect OCRL protein even in controls.

Conclusion:

Our findings extend the phenotypic spectrum caused by OCRL mutations and illustrate that there may be selective organ involvement in Lowe syndrome.

Zusammenfassung

Hintergrund:

Das Lowe-Syndrom ist eine X-chromosomal rezessive Erkrankung, die durch kongenitale Katarakt, mentale Retardierung und proximale Tubulopathie charakterisiert ist. Das Auftreten einer angeborenen Katarakt ist definitionsgemäß einKardinalsymptom dieser seltenen Erkrankung

Patient und Methodik:

Bei einem 13-jährigen Patienten mit dem typischen Phänotyp des Lowe-Syndromsdas aufgrund der fehlenden Augenbeteiligung nicht früher diagnostiziert wurde, führten wir eine OCRL –Gen-Analyse durch.

Ergebnisse:

Bei DNA-Analysen wurde eineStopp-Mutation in Exon 8 (c.C760T, p.Gln199X)identifiziert, die einen völligen Funktionsverlustdes OCRL-Proteins zur Folge haben sollte. EineSequenzanalyse der Eltern des Patienten sowieder maternalen Großeltern erbrachte den Hinweisauf eine de novo-Mutation bei der Mutter.Weiterhin identifizierten wir eine stille Variante(p.Arg35 = ) in Exon 2. Diese Variante konnten wirbei der Mutter und ihren 3 Schwestern, nichtaber in den Großeltern nachweisen, was auf einKeimzellmosaik bei einem der beidenGroßelternhindeutet. RNA aus Lymphozyten des Patientenbelegte das Vorliegen vollständiger OCRL -Transkripte.Mit dem Western-Blot mit Proben aus Lymphozyten konnten wir jedoch – selbst in Kontroll-Proben – kein OCRL-Protein nachweisen.

Schlussfolgerung:

Unsere Befunde erweiterndas phänotypische Spektrum dieser seltenen Erkrankungund machen deutlich, dass das Lowe-Syndrom mit einer selektiven Organbeteiligung einhergehen kann.

Key words

Lowe syndrome - congenital cataracts - OCRL gene - RNA analysis - translation reinitiation - alternative start codon

Schlüsselwörter

Lowe-Syndrom - kongenitaler Katarakt - OCRL-Gen - RNA-Analyse - Reinitiation der Translation - alternatives Start-Codon

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