Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations

Werf, Christine S. van der; Sribudiani, Yunia; Verheij, Joanne; Carroll, Matthew; O’Loughlin, Edward; Chen, Chien-Huan; Brooks, Alice S.; Liszewski, M. Kathryn; Atkinson, John P.; Hofstra, Robert

doi:10.1038/gim.2012.123

Cited by 33 publications

(36 citation statements)

References 18 publications

(30 reference statements)

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“…Furthermore, many male siblings of these patients die in early infancy because of gastrointestinal failure. [11][12][13][14] Compared with these patients, the spontaneous remission of CIPO and the unreported complication of Crohn's disease in our cases are quite atypical. It is possible that other atypical FLNA-deficient patients have been overlooked or misdiagnosed, which suggests the need to re-define the phenotypic diversity associated with FLNA deficiency.…”

Section: Discussionmentioning

confidence: 49%

“…11 In addition to the symptoms observed in females, some of these male survivors demonstrate gastrointestinal complications, including intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). [11][12][13][14] It is assumed that some male survivors carrying FLNA loss-offunction mutations retain sufficient FLNA protein expression to avoid the lethal effects; documented cases include splice-site mutations that produce both normal and aberrant FLNA mRNAs, 15,16 and truncating mutations in the 5' end that result in translation initiating from a second, downstream start codon. 12,14 Here, we present two male siblings with a 4-bp deletion in exon 40.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] It is assumed that some male survivors carrying FLNA loss-offunction mutations retain sufficient FLNA protein expression to avoid the lethal effects; documented cases include splice-site mutations that produce both normal and aberrant FLNA mRNAs, 15,16 and truncating mutations in the 5' end that result in translation initiating from a second, downstream start codon. 12,14 Here, we present two male siblings with a 4-bp deletion in exon 40. Within these siblings, inframe skipping of the mutated exon leads to the translation of functional FLNA protein, which could contribute to their survival.…”

Section: Introductionmentioning

confidence: 99%

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Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

et al. 2015

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Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and EhlersDanlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

et al. 2015

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“…However, it has been suggested that hypertrophic pyloric stenosis is not part of the general developmental defect of the gastrointestinal tract, but a physiological consequence from the attempts of the remnant small intestine to slow down the gastric emptying and improve absorptive capacity. CSBS patients usually have normal intellectual ability [19,20] and do not present Based on the literature available, it is difficult to assess if abnormal peristalsis is associated with CSBS pathogenesis, or if it is an independent event to the presence of a short bowel [3,22,23]. In most CSBS patients the bowel wall seems macroscopically normal, but an abnormal histology has been described in some patients.…”

Section: Clinical Presentationmentioning

confidence: 99%

“…For many years the underlying genetic cause of the disease was unknown. Recently, mutations in CLMP were identified to cause the autosomal recessive form of CSBS [2], and mutations in FLNA as the cause of the X-linked form of the disease [3]. These findings brought new insights into disease pathogenesis, but the mechanisms in which CLMP and FLNA contribute to intestinal elongation are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Congenital Short Bowel Syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation

Werf

Halim

Verheij

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Congenital Short Bowel Syndrome (CSBS) is a rare gastrointestinal disorder in which the mean length of the small intestine is substantially reduced when compared to its normal counterpart. Families with several affected members have been described and CSBS has been suggested to have a genetic basis. Recently, our group found mutations in CLMP as the cause of the recessive form of CSBS, and mutations in FLNA as the cause of the X-linked form of the disease. These findings have improved the quality of genetic counselling for CSBS patients and made prenatal diagnostics possible. Moreover, they provided a reliable starting point to further investigate the pathogenesis of CSBS, and to better understand the development of the small intestine. In this review, we present our current knowledge on CSBS and discuss hypotheses on how the recent genetic findings can help understand the cause of CSBS.

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Novel no‐stop FLNA mutation causes multi‐organ involvement in males

Oegema

Hulst

Theuns-Valks

et al. 2013

American J of Med Genetics Pt A

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Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.

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Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations

Cited by 33 publications

References 18 publications

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

Congenital Short Bowel Syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation

Novel no‐stop FLNA mutation causes multi‐organ involvement in males

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