Fischer, S.; Kohlhase, J.; Böhm, D.; Schweiger, B.; Hoffmann, Daniel; Heitmann, M.; Horsthemke, B.; Wieczorek, D.:

Biallelic loss of function of the promyelocytic leukaemia zinc finger (PLZF) gene causes severe skeletal defects and genital hypoplasia

In: Journal of Medical Genetics, Jg. 45 (2008), S. 731-737
Zeitschriftenaufsatz / Fach: Medizin; Biologie; Informatik
Background: Deletions of 11q23 are associated with mental retardation, craniofacial dysmorphism, microcephaly and short stature. We present a patient with similar clinical findings, in addition to absence of the thumbs, hypoplasia of the radii and ulnae, additional vertebrae and ribs, retarded bone age and genital hypoplasia.

Methods: Genomic DNA from the patient was screened for chromosomal imbalances by array-based comparative genomic hybridisation. DNA sequence analyses and reporter gene assays were performed in order to identify candidate gene mutations.

Results: The patient has an ~8 Mbp de novo deletion on the paternal chromosome 11, which includes the promyelocytic leukaemia zinc-finger gene (PLZF, ZBTB16; OMIM 176797 [OMIM] ). The maternal PLZF allele harbours a recessive missense mutation (c.1849A->G), which leads to the substitution of a highly conserved methionine by valine (p.Met617Val) within a zinc-finger motif. Taking into account specific alpha-helical propensities of Val and Met, this mutation is likely to destabilise the alpha helix of the zinc finger that forms the contact with the DNA duplex, thus affecting the biological function as shown by reporter-gene assays.

Discussion: The PLZF gene is one of five partners fused to the retinoic acid receptor {alpha} in acute promyelocytic leukaemia. We describe the first patient, to our knowledge, with a germline mutation of PLZF. Our findings as well as observations in Plzf-deficient mice indicate that PLZF is a key regulator of skeletal and male germline development. Furthermore, this case highlights the importance of searching for a recessive mutation on the non-deleted chromosome in patients with a microdeletion and atypical clinical findings.

Deletions of the chromosomal region 11q23 are associated with mental retardation, craniofacial dysmorphism, microcephaly and short stature. In 2002, we reported on a male patient with similar clinical features, in addition to absence of the thumbs, a/hypoplasia of the radius, hypoplasia of the ulnae, retarded bone age and hypoplastic genitalia, and suggested that this boy represents a new multiple congenital anomaly/mental retardation (MCA/MR) syndrome.1 The results of chromosomal analysis and low-resolution comparative genomic hybridisation for this child had been normal.

Within the chromosomal region 11q23, the promyelocytic leukaemia zinc finger (PLZF, ZBTB16; OMIM 176797 [OMIM] ) gene encodes a DNA sequence-specific transcriptional repressor. It was first discovered as the fusion partner of the retinoic acid receptor-alpha (RARA) gene on chromosome 17 in a patient with acute promyelocytic leukaemia and a translocation t(11;17)(q23;21).2 The fusion protein blocks retinoic acid-induced differentiation of haematopoietic cells.3 Mutations in mice have revealed that PLZF also plays an important role in skeletal development and spermatogonial stem-cell maintenance.4–7 Hitherto, PLZF germline mutations have not yet been described in humans.

We carried out comparative genomic hybridisation (CGH) of a 244K oligonucleotide array and have now identified in this patient an ~8 Mbp interstitial deletion in 11q23, which includes the PLZF gene. The deletion unmasks a recessive missense mutation (c.1849A->G) of the remaining PLZF allele. In summary, our findings show that biallelic loss of function of PLZF causes severe skeletal defects and genital hypoplasia, which resemble those of Plzf-deficient mice.