Sensenbrenner syndrome
Encyclopedia
Sensenbrenner syndrome is a rare (less than 20 cases reported by 2010) multisystem disease first described in 1975. 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), IFT43 - a subunit of the IFT complex A machinery of primary cilia
, and WDR35 (IFT121: TULP4)
It is also known as Sensenbrenner-Dorst-Owens syndrome, Levin Syndrome I and cranioectodermal dysplasia (CED)
Electroretinography
shows gross abnormalities.
Two fetuses of 19 and 23 weeks gestation have also been reported. 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.
s (kDa). It is a member of the WD repeat protein family.
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.
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. 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).
-2 while the retrograde movement of particles back to the cell body is driven by cytoplasmic dynein
1b/2
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.
Intraflagellar transport
Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation 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...
(IFT)122 (WDR10), IFT43 - a subunit of the IFT complex A machinery of primary cilia
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
, and WDR35 (IFT121: TULP4)
It is also known as Sensenbrenner-Dorst-Owens syndrome, Levin Syndrome I and cranioectodermal dysplasia (CED)
Clinical features
These are pleomorphic and include- dolichocephalyDolichocephalyDolichocephaly is another word for scaphocephaly, a condition where the head is longer than would be expected, relative to the width of the head.It can present in cases of Sensenbrenner syndrome, Sotos syndrome, as well as Marfan syndrome.-External links:...
(with or without sagittal suture synostosis) - microcephalyMicrocephalyMicrocephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
- pre- and postnatal growth retardation
- brachydactylyBrachydactylyBrachydactyly , is a medical term which literally means "shortness of the fingers and toes" . The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, usually dominant trait...
- narrow thorax
- rhizomelic dwarfism
- epicanthal folds
- hypodontiaHypodontiaIn dentistry, hypodontia is the condition at which the patient has missing teeth as a result of their failure to develop. Hypodontia describes a situation where the patient is missing up to 6 teeth, excluding the 3rd molars. Missing third molars occur in 9-30% of population...
and/or microdontiaMicrodontiaMicrodontia is a condition in which teeth appear smaller than normal. In the generalized form, all teeth are involved. In the localized form, only a few teeth are involved. The most common teeth affected are the upper lateral incisors and third molars... - sparse, slow-growing, hyperpigmented, fine hair
- nail dysplasia
- hypohydrosis
- chronic renal failure
- heart defects
- liver fibrosis
- visual deficits
- photophobia
- hypoplasia of the posterior corpus callosumCorpus callosumThe corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
- aberrant calcium homeostasis
Electroretinography
Electroretinography
Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors , inner retinal cells , and the ganglion cells. Electrodes are usually placed on the cornea and the skin near the eye, although it is possible to record the ERG from skin electrodes...
shows gross abnormalities.
Two fetuses of 19 and 23 weeks gestation have also been reported. 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.
Genetics
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 kiloDaltonDalton
Dalton may refer to:-In Canada:* Dalton, Algoma District, Ontario* Dalton Armoury, a Canadian Forces facility primarily used by the Queen's Own Rifles of Canada- In the United Kingdom :* Dalton, Cumbria, England* Dalton, Dumfries and Galloway, Scotland...
s (kDa). It is a member of the WD repeat protein family.
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.
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. 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
Sonic hedgehog
Sonic hedgehog homolog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog and Indian hedgehog . SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as...
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).
Pathology
The visual defects are due to photoreceptor dystrophy. The chronic renal failure is due to tubulointerstitial nephropathy. The liver fibrosis is secondary to ductal plate malformation.Pathophysiology
The IFT machinery is organized in two structural complexes - A and B. These complexs 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 kinesinKinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP . The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular...
-2 while the retrograde movement of particles back to the cell body is driven by cytoplasmic dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
1b/2
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.