Sensenbrenner syndrome

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Sensenbrenner syndrome
Other namesCranioectodermal dysplasia
Autosomal recessive - en.svg
This condition is inherited in an autosomal recessive manner

Sensenbrenner syndrome (OMIM #218330) is a rare (less than 20 cases reported by 2010) multisystem disease first described by Judith A. Sensenbrenner in 1975. [1] It is inherited in an autosomal recessive fashion, and a number of genes appear to be responsible. Three genes responsible have been identified: intraflagellar transport (IFT)122 (WDR10), [2] IFT43—a subunit of the IFT complex A machinery of primary cilia, [3] and WDR35 (IFT121: TULP4) [4]

Contents

It is also known as Sensenbrenner–Dorst–Owens syndrome, Levin syndrome I and cranioectodermal dysplasia (CED)

Presentation

These are pleomorphic and include[ citation needed ]

Electroretinography shows gross abnormalities.

Two fetuses of 19 and 23 weeks gestation have also been reported. [5] They showed acromesomelic shortening, craniofacial characteristics with absence of craniosynostosis, small kidneys with tubular and glomerular microscopic cysts, persistent ductal plate with portal fibrosis in the liver, small adrenals, an enlarged cisterna magna and a posterior fossa cyst.

Cause

The gene IFT122 is located on the long arm of chromosome 3 (3q21-3q24). The gene lies on the Watson (plus) strand and is 80,047 bases in length. The encoded protein has 1241 amino acids and a predicted weight of 141.825 kiloDaltons (kDa). It is a member of the WD repeat protein family.[ citation needed ]

WDR35 is also a member of the WD repeat protein family. The gene is located on the short arm of chromosome 2 (2p24.1–2p24.3) The gene lies on the Crick (minus) strand and is 79,745 bases in length. The encoded protein is 1181 amino acids in length and its predicted molecular weight is 133.547 kiloDaltons.[ citation needed ]

The gene IFT43 lies on the Watson (plus) strand of the long arm of chromosome 14 (14q24.3).

A mouse model for IFT122 has been created. [6] Mutants deficient in IFT122 show multiple developmental defects (many are lethal), including exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively.

Impairment of the Sonic hedgehog pathway was apparent in both neural tube patterning (expansion of motoneurons and rostrocaudal level-dependent contraction or expansion of the dorsolateral interneurons) and limb patterning (ectrosyndactyly).

Pathophysiology

The IFT machinery is organized in two structural complexes — A and B. These complexes are involved in the coordinated movement of macromolecular cargo from the basal body along axonemal microtubules to the cilium tip and back again. The anterograde movement of IFT particles out to the distal tip of cilia and flagella is driven by kinesin-2 while the retrograde movement of particles back to the cell body is driven by cytoplasmic dynein 1b/2[ citation needed ]

The IFT-A protein complex is involved in retrograde ciliary transport. Disruption of IFT43 disturbs transport from the ciliary tip to the base. Anterograde transport in the opposite direction remains normal resulting in accumulation of the IFT complex B proteins in the ciliary tip.[ citation needed ]

Pathology

The visual defects are due to photoreceptor dystrophy. The chronic kidney failure is due to tubulointerstitial nephropathy. The liver fibrosis is secondary to ductal plate malformation.

Diagnosis

Treatment

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Intraflagellar transport

Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface. Plasmodium falciparum cilia and the sperm flagella of Drosophila are examples of cilia that assemble in the cytoplasm and do not require IFT. The process of IFT involves movement of large protein complexes called IFT particles or trains from the cell body to the ciliary tip and followed by their return to the cell body. The outward or anterograde movement is powered by kinesin-2 while the inward or retrograde movement is powered by cytoplasmic dynein 2/1b. The IFT particles are composed of about 20 proteins organized in two subcomplexes called complex A and B.

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Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy. Its incidence has been estimated to be 0.9 cases per million people in the United States, and 1 in 50,000 births in Canada.

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IFT88

Intraflagellar transport protein 88 homolog is a protein that in humans is encoded by the IFT88 gene.

WDR62

WD repeat-containing protein 62 is a protein that in humans is encoded by the WDR62 gene.

KIF17

Kinesin-like protein KIF17 is a protein that in humans is encoded by the KIF17 gene. KIF17 and its close relative, C. elegans OSM-3, are members of the kinesin-2 family of plus-end directed microtubule-based motor proteins. In contrast to heterotrimeric kinesin-2 motors, however, KIF17 and OSM-3 form distinct homodimeric complexes. Homodimeric kinesin-2 has been implicated in the transport of NMDA receptors along dendrites for delivery to the dendritic membrane, whereas both heterotrimeric and homodimeric kinesin-2 motors function cooperatively in anterograde intraflagellar transport (IFT) and cilium biogenesis.

IFT20

Intraflagellar transport protein 20 homolog is a protein that in humans is encoded by the IFT20 gene. The gene is composed of 6 exons and is located on human chromosome 17p11.1. This gene is expressed in human brain, lung, kidney and pancreas, and lower expression were also detected in human placenta, liver, thymus, prostate and testis.

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A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

IFT80

Intraflagellar transport protein 80 homolog (IFT80), also known as WD repeat-containing protein 56, is a protein that in humans is encoded by the IFT80 gene.

Ciliogenesis is defined as the building of the cell's antenna or extracellular fluid mediation mechanism. It includes the assembly and disassembly of the cilia during the cell cycle. Cilia are important organelles of cells and are involved in numerous activities such as cell signaling, processing developmental signals, and directing the flow of fluids such as mucus over and around cells. Due to the importance of these cell processes, defects in ciliogenesis can lead to numerous human diseases related to non-functioning cilia. Ciliogenesis may also play a role in the development of left/right handedness in humans.

IFT140

IFT140, Intraflagellar transport 140 homolog, is a protein that in humans is encoded by the IFT140 gene. The gene product forms a core component of IFT-A complex which is indipensible for retrograde intraflagellar transport within the primary cilium.

RVxP motif is a protein motif involved in localizing proteins into cilia.

References

  1. ↑ Sensenbrenner JA, Dorst JP, Owens RP (1975). "New syndrome of skeletal, dental and hair anomalies". Birth Defects Orig. Artic. Ser. 11 (2): 372–9. PMID   1227553.
  2. ↑ Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW (2010). "Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene". Am. J. Hum. Genet. 86 (6): 949–56. doi:10.1016/j.ajhg.2010.04.012. PMC   3032067 . PMID   20493458.
  3. ↑ Arts HH, Bongers EM, Mans DA, van Beersum SE, Oud MM, Bolat E, Spruijt L, Cornelissen EA, Schuurs-Hoeijmakers JH, de Leeuw N, Cormier-Daire V, Brunner HG, Knoers NV, Roepman R (2011). "C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome". J. Med. Genet. 48 (6): 390–5. doi:10.1136/jmg.2011.088864. PMID   21378380. S2CID   6073572.
  4. ↑ Gilissen C, Arts HH, Hoischen A, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG (2010). "Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome". Am. J. Hum. Genet. 87 (3): 418–23. doi:10.1016/j.ajhg.2010.08.004. PMC   2933349 . PMID   20817137.
  5. ↑ Konstantinidou AE, Fryssira H, Sifakis S, Karadimas C, Kaminopetros P, Agrogiannis G, Velonis S, Nikkels PG, Patsouris E (2009). "Cranioectodermal dysplasia: a probable ciliopathy". Am. J. Med. Genet. A. 149A (10): 2206–11. doi:10.1002/ajmg.a.33013. PMID   19760621. S2CID   31080779.
  6. ↑ Cortellino S, Wang C, Wang B, Bassi MR, Caretti E, Champeval D, Calmont A, Jarnik M, Burch J, Zaret KS, Larue L, Bellacosa A (2009). "Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4". Dev. Biol. 325 (1): 225–37. doi:10.1016/j.ydbio.2008.10.020. PMC   2645042 . PMID   19000668.
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