Mutations in the WNT3 gene cause TAS

A mutation in the WNT3 gene has been shown to cause Tetra-Amelia Syndrome [TAS] among members of one large family from Turkey. This mutation, which occurs in both copies of the WNT3 gene in each cell, replaces one protein building block (amino acid) with a premature stop signal in the instructions for making the WNT3 protein. This mutation is written as ‘Gln83Ter or Q83X’.

Researchers believe that the Gln83Ter mutation results in the production of an abnormally short, nonfunctional version of the WNT3 protein. Loss of the WNT3 protein disrupts normal limb formation before birth and leads to the other serious birth defects associated with Tetra-Amelia Syndrome [TAS].

Source: www.ghr.nlm.nih.gov

Normal Function of WNT3 gene .....

The WNT3 gene is part of a large family of WNT genes, which play critical roles in development before birth. WNT genes provide instructions for making proteins that participate in chemical signaling pathways in the body. These pathways control the activity of certain genes and regulate the interactions between cells during embryonic development.

Research in animals indicates that the protein produced from the WNT3 gene is critical for the outgrowth of the limbs in the developing embryo. The WNT3 protein also appears to play an important role in determining the anterior-posterior axis (the imaginary line that runs from head to tail in animals) during the earliest stages of embryonic development. Additionally, the effects of mutations in the human WNT3 gene suggest that the protein may be involved in the normal formation of the facial features, head, heart, lungs, nervous system, skeleton, and genitalia.

Source: www.ghr.nlm.nih.gov

WNT3 gene share characteristics with other genes

The WNT3 gene belongs to a family of genes called ‘Endogenous Ligands’. It also belongs to a family of genes called WNT (wingless-type MMTV integration site family).

WNT3 Gene ...... Location

Cytogenetic Location: 17q21

Molecular Location: Chromosome 17

Base pairs (bp) 44,839,871 ~ 44,896,125

The WNT3 gene is located on the long (q) arm of chromosome 17 at position 21, more precisely from bp 44,839,871 ~ 44,896,125.

The Gene …… WNT3

Official Name: wingless-type MMTV integration site family, member 3

Official Symbol: WNT3 

Other Names:

·       INT4

·       Oncogene INT4

·       Proto-oncogene protein Wnt-3

·       WNT3_HUMAN

·       WNT-3 proto-oncogene protein

Gene .....

From one large family of affedted Tetra Amelis Syndrome [TAS] researcher found mutation in the WNT3 Gene.

WNT3 gene is part of a family of WNT genes which play critical roles in development before birth.

The protein produced from the WNT3 gene is involved in the formation of the limbs and other body systems during embryonic development.

Mutations in the WNT3 gene prevent cells from producing functional WNT3 protein which disrupts normal formation of limb and leads to the other serious birth defects associated with Tetra Amelia Syndrome [TAS].

In other affected families, the cause of Tetra Amelia Syndrome [TAS] has not been determined. Researchers believe that unidentified mutations in WNT3 or other genes involved in the development of limb are probably the reason behind this Tetra Amelia Syndrome [TAS].

Then mutation detection frequency is unknown as only a limited number of families have been studied.

Diagnosis .....

Clinical Diagnosis

Tetra Amelia Syndrome [TAS] is characterized by the complete absence of all four limbs (Figure 1). The diagnosis of Tetra Amelia Syndrome can be established clinically and is usually made on routine Prenatal Ultrasonography (Figure 2).

Figure 1. Postmortem radiograph of fetus with tetra-amelia syndrome demonstrating absence of all four limbs (without defects of scapulae and clavicles)

Figure 2. Prenatal ultrasonography showing fetus without limbs

Testing

Cytogenetic analyses, performed in some of the reported cases, showed normal karyotypes without ‘premature centromere separation’ (Roberts syndrome: www.ncbi.nlm.nih.gov/books/NBK1153).

Molecular Genetic Testing

Gene: WNT3 is the only gene in which mutations are known to cause Tetra Amelia Syndrome [TAS] in one family [Niemann et al 2004].

Evidence for Locus Heterogeneity: Genetic heterogeneity of Tetra Amelia Syndrome [TAS] is strongly suggested by Krahn et al [2005]& Sousa et al [2008], who described fetuses with tetra-amelia, agenesis of both lungs, cleft lip/cleft palate and micrognathia in whom no mutations were identified in the coding exon regions of WNT3 and other candidate genes.

Clinical Testing

Summary of Molecular Genetic Testing Used in Tetra-Amelia Syndrome

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
WNT3	Sequence analysis	p.Gln83X (c.247C>T) 2	Unknown 3	Clinical
	Deletion/ Duplication Analysis 4	Deletion/Duplication of one or more ‘exons’ or the whole gene	Unknown none reported 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Only one family studied to date [Niemann et al 2004]

3. Percentage of detectable mutations is unknown, as a WNT3 mutation has so far been demonstrated in only one family with tetra-amelia syndrome [Niemann et al 2004].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), andchromosomal microarray (CMA) that includes this gene/chromosome segment.

5. No deletions or duplications of WNT3 have been reported to cause tetra-amelia syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Symptoms ....

Tetra Amelia Syndrome [TAS] is characterized by the complete absence of all 4 limbs and following anomalies may involve:

Cranium & Face

¶      Cleft Lip/Cleft Palate

¶      Micrognathia

¶      Microtia

¶      Single Naris

¶      Choanal Atresia

¶      Absence Of Nose

Eyes

¶      Microphthalmia

¶      Microcornea

¶      Cataract

¶      Coloboma

¶      Palpebral Fusion

Urogenital System

¶      Renal Agenesis

¶      Persistence Of Cloaca

¶      Absence Of External Genitalia

¶      Atresia Of Vagina

Anus: Atresia

Heart

Lungs: Hypoplasia/aplasia

Skeleton

¶      Hypoplasia/absence of pelvic bones

¶      Absence of ribs, absence of vertebrae

 Central nervous system

¶      Agenesis Of Olfactory Nerves,

¶      Agenesis Of Optic Nerves

¶      Agenesis Of Corpus Callosum

¶      Hydrocephalus

As we discussed earlier the affected infants are often stillborn or die shortly after birth.

Inheritance ……

Tetra-amelia syndrome is inherited in an ‘autosomal recessive manner’. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. 

How common is Tetra-Amelia Syndrome?

Tetra-Amelia Syndrome is an extremely rare disorder and has been described in only 5 families of different ethnic backgrounds (Arab, Morocco, Syrian-Aramatic, Australia, Japan) till date.

So far 2 famous personalities have survived Tetra Amelia Syndrome (TAS):

1.  Nicholas (Nick) Vujicic [Motivational Speaker]

2.  Hirotada Ototake [Japanese Author & Sports Journalist]

Tetra-Amelia Syndrome ... What is it ???

Tetra-Amelia Syndrome (TAS) is a very rare disorder characterized by the absence of all the four limbs.

‘Tetra’ is a Greek word for ‘Four’

‘Amelia’ refers to the failure of development of an arm/leg before birth.

TAS can also cause severe malformations of other parts of the body including the head & face, heart, nervous system, skeleton, and genitalia.

The lungs are underdeveloped in many cases which makes breathing difficult or impossible.

Most of the children with Tetra-Amelia Syndrome (TAS), having such serious medical problems, are stillborn or die shortly after birth.

Life Without Limbs ... Tetra Amelia Syndrome

Imagine being born without hands !!! No arms to hug your loved one, wrap around a friend ¾ no fingers to experience touch ¾ no way to lift or carry things.

Picture your life without the ability to walk, run or even stand in your two feet.

Now put both the scenario together ¾ No Arms … No Legs ……… Perplexed !!!

How much more difficult would life be if you were living without arms or legs? What would you do? How would that affect your everyday life?

In my last video meet Mr. Nick Vujicic (pronounced ‘Vooy-cheech), born in 1982 in Brisbane, Australia, without any medical explanation or warning, Nicholas Vujicic came into the world with neither arms nor legs. Imagine the shock his parents felt when they saw their first-born brand new baby boy for the first time, only to find he was what the world would consider abnormal. 

Nick was born with Tetra-Amelia Syndrome where the arms & legs were not developed at all !!!