Response to PM from nightflight

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Arion Mgmt

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Dec 1, 2002
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I recieved this PM below from nightflight suggesting all of ACH cases in humans has been proven to be solely derived from the paternal side, ie, sperm only. This paper she sited I have listed below and it is available to read as a pdf, and other formats free. It was written in 1998.

My answer is very detailed and very long so get a drink or whatever poison you take and sit awhile.

I am assuming she read the entire paper and understands the specific mutation they are discussing in the paper. I have this paper and I am giving the link below so all can read it.

FYI, the gene FGFR3 is not sex-linked and is on an autosome, meaning it is not on the X or Y chromosome. What this paper is explaining is in their 40 cases of ACH, the chromosome with this specific mutation derived from the father autosome not the mother. However when a female ACH is born she can grow up to pass the defective gen onto 50% of her children irrespective of sex.

I do not know if Colleen was thinking all the dwarfisms in the Miniatures are strickly sire based but I hope you really read what I wrote below and try to read as much as you can in the links to understand my opinion as to the novelty of FGFR3 1138 and ACH, and how it is not very convincing at all to be the cause of the dwarfisms seen in the Miniatures from de novo mutations in sire's sperm.

from Colleen

"Thank you for your reply to my question =).

I do not know of any scientific study that has proven that the mutation only occurs in the sperm during spermatogenesis. Since it is a non-sex linked disease, and it involves a gene that both males and females carry, it has just as much chance of sporadically mutating in the female as in the male.
Not proven, but strongly suggested. I just googled this paper up, no sci-searches on this computer, so I can't speak to it's quality, but good ones are out there. Not to say that mutation can only occur paternally, just when you consider the process of gamete formation that there are more chances for replication errors during spermatogenesis.

Title Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome

Author(s) Douglas J. Wilkin, Jinny K. Szabo, Rhoda Cameron, Shirley Henderson, Gary A. Bellus, Michelle L. Mack, Ilkka Kaitila, John Loughlin, Arnold Munnich, Bryan Sykes, Jacky Bonaventure, and Clair A. Francomano

The American Journal of Human Genetics, volume 63 (1998), pages 711–716

Not equine related, but interesting in it's own right. If you have a tame undergrad to spare there is more out there. =)

Many thanks for your time,


The paper by Wilkin describes 40 cases involving 99 families with a sporadic case of ACH resulting from the SPECIFIC mutation of the single base pair 1138 mutation of G(guanine) to A(adenine) or G(guanine) to C(cytosine), resulting in a change of amino acid 380 from glycine to arginine. Therfore resulting in this specific ACH mutation within FGFR3 ONLY to be derived from the father, and that it also notes that increase in age in men causes a higher mutation rate versus youger men.

I am quoting the paper summary

"More than 97% of achondroplasia cases are caused by

one of two mutations (G1138A and G1138C) in the

fibroblast growth factor receptor 3 (FGFR3) gene, which

results in a specific amino acid substitution, G380R. Sporadic

cases of achondroplasia have been associated with

advanced paternal age, suggesting that these mutations

occur preferentially during spermatogenesis. We have

determined the parental origin of the achondroplasia

mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms

were identified in the FGFR3 gene, within

close proximity to the achondroplasia mutation site.

Ninety-nine families, each with a sporadic case of achondroplasia

in a child, were analyzed in this study. In this

population, the achondroplasia mutation occurred on

the paternal chromosome in all 40 cases in which parental

origin was unambiguous. This observation is consistent

with the clinical observation of advanced paternal

age resulting in new cases of achondroplasia and suggests

that factors influencing DNA replication or repair

during spermatogenesis, but not during oogenesis, may

predispose to the occurrence of the G1138 FGFR3


The paper explains it is strong "suggestive" evidence for only this mutation, and I agree, for THIS mutation only, and in HUMANS only. The authors only looked at this mutation, all of the other FGFR3 mutations resulting in ACH or other types of human dwarfism have not been studied for this, yet, that I have found. In the paper below regarding age and increase risk, they do link a possibility with FGFR2 and specifically Apert Syndrome. There could be some paper out there somewhere that has done a similar study on a different mutation of FGFR3.

I have listed another overview paper that goes over a large amount of info that you all are encouraged to read. And in this paper it has statisical information showing the increases in mutation rates of spermatozoa in men with increasing age.

I am also listing below another link to another current overview of ACH studies and findings and in that it states as I will quote so you do not miss it becuase the overview is rather lengthy.

"Using modern diagnostic criteria, Gardner (1977) estimated the mutation rate at 0.000014. Orioli et al. (1986) reported on the frequency of skeletal dysplasias among 349,470 births (live and stillbirths). The prevalence rate for achondroplasia was between 0.5 and 1.5/10,000 births. The mutation rate was estimated to be between 1.72 and 5.57 x 10(-5) per gamete per generation. The stated range is a consequence of the uncertainty of diagnosis in some cases. (The thanatophoric dysplasia/achondrogenesis group had a prevalence between 0.2 and 0.5/10,000 births. Osteogenesis imperfecta had a prevalence of 0.4/10,000 births. Only 1 case of diastrophic dysplasia was identified.) In the county of Fyn in Denmark, Andersen and Hauge (1989) determined the prevalence of generalized bone dysplasias by study of all children born in a 14-year period. The figures, which they referred to as 'point-prevalence at birth,' showed that achondroplasia was less common than generally thought (1.3 per 100,000), while osteogenesis imperfecta (21.8), multiple epiphyseal dysplasia tarda (9.0), achondrogenesis (6.4), osteopetrosis (5.1), and thanatophoric dysplasia (3.8) were found to be more frequent. Stoll et al. (1989) found a mutation rate of 3.3 x 10(-5) per gamete per generation. In Spain, Martinez-Frias et al. (1991) found a frequency of achondroplasia of 2.53 per 100,000 live births. Total prevalence of autosomal dominant malformation syndromes was 12.1 per 100,000 live births. "So if you were to apply these same statistical calculations to another mammal, to determine if this ACH mutation is occuring de novo from sporadic mutations or if it is being inherited recessively, which is what you do with a population, you would see that our dwarf type 1 alone numbers are much higher percentages

Given this population statistics information above and applying the thought of just the type 1 dwarfism in ANY OTHER MAMMAL you would expect to see de novo mutations causing ACH to be approx. 2.5 cases per 100,000 live births. It is not seen. Unfortunately, I think we have quite a higher number than 2.5 births of just type 1 dwarfs in 100,000 Miniature births. I do not know how many Miniatures are born world wide each yr. but it is not 100,000.

I dont even think there are 250,000 miniatures TOTAL world wide. That being said it would mean we would have to be having at least 100,000 foals born a year and only see 2.5 dwarfs of type 1 born. Or more realistically have 1,000 births and have 0.025 dwarf type 1 born per year. THis does not even count the other types of dwarfism I am seeing.

Again, my numbers in fairly large variable pedigree population of Miniatures horses, calculations so far in the miniatures that I have done, the type 1 dwarfism is showing a CLASSICAL Mendelian inheritance pattern consistent with the mutation being a homozygous autosomal recessive trait. The other types I have not done yet, due to the difficulty in getting samples and information from owners.

So, with this knowledge and knowledge that there is only one other equine breed that has seen possibly some type of inherited dwarfism( ie Fresians, which is speculative right now as autosomal recessive as well), it would very narrow minded to think that the large number of dwarfs, comparitively, seen in the Miniatures are strickly de novo sire based. Since dwarfs were known to be used for breeding decades ago. I can list over 100 type 1 dwarfs that I have seen since 1978, I unfortunately dont have all those as samples or I would might already have answers. I recieved last yr alone 10 type 1 dwarf foal blood samples or bodies to my lab that were born last year. That is not close to the number I see on the internet discussed that were born last year asking about info.

There is no other known mammal that exists that shows the FGFR3 1138 mutation to be paternally derived, AND that there is no known information that I can find that suggests also to have the increased mutation rate of FGFR3 in germline cells of other male mammals. Consequently, the dwarfisms found so far in other mammals that have been sequenced and characterized have yet to show characteristics of being caused by a mutation in FGFR3 the same seen in the humans, or even more specifically ACH 1138 mutation, meaning paternally derived, and increased risk with age. This does not include knockout lab mice and rats used for research in dwarfism. It is right now novel to itself from natural occurance.

The Dexter dwarf is not caused by a mutation in FGFR3, nor is the dwarfism in Japanese brown cattle caused by FGFR3.

There are known to be a mirad of other mutations within the FGFR3 that produces ACH or other ACH like diseases, all with various characteristics and names. And it would not suprise me if some other mutations in FGFR3 or FGFR1 or FGFR2, show germline cause from the male, since the male has more cell divisions in the germline production than the female. But again, the characterisitcs of this mutation of ACH 1138 is only seen in humans so far from what I have read.

quoting from one of the overviews--

"In discussing 'male-driven evolution' and the evidence for a generally higher mutation rate in males than in females, Crow (1997) stated that the number of cell divisions required to generate sperm cells in a 30-year-old man is estimated at 400; the number of cell divisions that generate an egg is 24, irrespective of age. If mutation rates are proportional to the cell divisions, the male-to-female ratio should equal 17. In fact, the data show a higher ratio, as if mutation rates increase at a higher rate than the number of replications would predict--not surprising if fidelity of transcription and efficiency of repair mechanisms diminish with age. Studies in male and female birds by Ellegren and Fridolfsson (1997) appeared to support male-driven evolution of DNA sequences in birds. "

I hope this answerd your question Colleen, I just felt this needed to be posted here since there is so much info in this response that will help others to understand more about the complexities of genetics.

I hope you continue looking for all the info you can find.

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