<i>PBX1</i>haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans

Tanno, Pauline Le; Breton, Julie; Bidart, Marie; Satre, Véronique; Harbuz, Radu; Ray, Pierre F.; Bosson, Caroline; Dieterich, Klaus; Jaillard, Sylvie; Odent, S.; Poke, Gemma; Beddow, Rachel; Digilio, Maria C.; Novelli, Antonio; Bernardini, Laura; Pisanti, Maria Antonietta; Mackenroth, Luisa; Hackmann, Karl; Vogel, Ida; Christensen, Rikke; Fokstuen, Siv; Béna, Frédérique; Amblard, Florence; Devillard, Françoise; Vieville, Gaëlle; Apostolou, Alexia; Jouk, Pierre‐Simon; Guebre-Egziabher, Fitsum; Sartelet, Hervé; Coutton, Charles

doi:10.1136/jmedgenet-2016-104435

Cited by 51 publications

(69 citation statements)

References 45 publications

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“…Genital abnormalities are commonly reported in male patients with PBX1 mutations (10/14), with the phenotypic spectrum ranging from cryptorchidism to partial development of female internal and/or external genitalia (Alankarage et al, ; Eozenou et al, ; Kia et al, ; Riedhammer et al, ; Slavotinek et al, ; Le Tanno et al, ). Interestingly, the second affected sibling (II‐5; 46, XY) presented here showed complete sex reversal of both internal and external organs, without any signs of male gonad development (no streak gonad).…”

Section: Discussionmentioning

confidence: 99%

“…De novo mutations in PBX1 were first identified as a cause of CAKUT in humans in 2017 (MIM: 617641) following earlier work demonstrating renal hypoplasia, renal ectopia, and renal agenesis in a Pbx1 −/− mouse model (Heidet et al, ; Le Tanno et al, ; Schnabel, Selleri, & Cleary, ; Slavotinek et al, ). The reported heterozygous disease causing mutations in PBX1 include partial and complete gene deletions, truncating, splice site and missense variants (Figure S1).…”

Section: Introductionmentioning

confidence: 99%

“…These include facial dysmorphism, and anatomic abnormalities of the ear, genitalia, heart, and lung. Developmental delay/intellectual disability is common, and growth restriction and hearing loss have also been reported (Table S1; Alankarage et al, ; Eozenou et al, ; Heidet et al, ; Kia, Sarafoglou, Mooganayakanakote Siddappa, & Roberts, ; Riedhammer et al, ; Slavotinek et al, ; Sun et al, ; Le Tanno et al, ). We present two cases of perinatal death, from independent pregnancies in one family, with a recurrent disease‐causing mutation in PBX1 due to paternal mosaicism for the mutation.…”

Section: Introductionmentioning

confidence: 99%

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Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Arts

Garland

Byrne

et al. 2020

American J of Med Genetics Pt A

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Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Arts

Garland

Byrne

et al. 2020

American J of Med Genetics Pt A

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“…Chromosomal rearrangements encompassing PBX1 , t(1;19)(q23;p13.3), are associated with lymphoblastic leukemia (Williams et al, ). Recently, mutations involving the human PBX1 gene have been described as a cause of congenital anomalies of the kidney and urinary tract (CAKUT; Heidet et al, ; Le Tanno et al, ). In this study, we identified a specific de novo PBX1 missense mutation in the highly conserved TALE homodomain associated with a lack of testis‐determination.…”

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confidence: 99%

The TALE homeodomain of PBX1 is involved in human primary testis‐determination

et al. 2019

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Human sex‐determination is a poorly understood genetic process, where gonad development depends on a cell fate decision that occurs in a somatic cell to commit to Sertoli (male) or granulosa (female) cells. A lack of testis‐determination in the human results in 46,XY gonadal dysgenesis. A minority of these cases is explained by mutations in genes known to be involved in sex‐determination. Here, we identified a de novo missense mutation, p.Arg235Gln in the highly conserved TALE homeodomain of the transcription factor Pre‐B‐Cell Leukemia Transcription Factor 1 (PBX1) in a child with 46,XY gonadal dysgenesis and radiocubital synostosis. This mutation, within the nuclear localization signal of the protein, modifies the ability of the PBX1 protein to localize to the nucleus. The mutation abolishes the physical interaction of PBX1 with two proteins known to be involved in testis‐determination, CBX2 and EMX2. These results provide a mechanism whereby this mutation results specifically in the absence of testis‐determination.

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“…Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3–6 per 1000 live births, accounting for most cases of paediatric end-stage kidney disease 1 . However, the molecular basis of CAKUT and anomalies of the external genitalia is poorly understood.…”

mentioning

confidence: 99%

Coexistent duplication of urethra and a refluxing ectopic ureter presenting as recurrent epididymo-orchitis in a child

Mohamed¹,

Jehangir

2017

BMJ Case Reports

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Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3-6 per 1000 live births, accounting for most cases of paediatric end-stage kidney disease. However, the molecular basis of CAKUT and anomalies of the external genitalia is poorly understood. We, herein, describe a case with left recurrent epididymo-orchitis with a coexistent urethral duplication and an ectopic ureter with an ipsilateral non-functioning kidney, which is, to the best of our knowledge, the first reported case of its kind. This case may bring about a paradigm shift in our comprehension of the development of the two entities. Understanding the pathogenesis may help develop preventive and renal preservation strategies. The Sonic hedgehog gene and bone morphogenetic protein 4 play crucial roles in preventing anomalies of the ureters and the external genitalia. In this article, we look at possible molecular pathways that could explain the synchronicity of this rare entity.

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PBX1haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans

Cited by 51 publications

References 45 publications

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

The TALE homeodomain of PBX1 is involved in human primary testis‐determination

Coexistent duplication of urethra and a refluxing ectopic ureter presenting as recurrent epididymo-orchitis in a child

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