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CORRESPONDENCE

Response to “De Novo Mutation of the TGFB3Latency-Associated Peptide Domain in a PatientWith Overgrowth and Loeys–Dietz SyndromeFeatures”

Hugh Young Rienhoff Jr.*CHORI, San Carlos, California

Manuscript Received: 6 March 2014; Manuscript Accepted: 7 April 2014

How to Cite this Article:Rienhoff HY. 2014. Response to “de novo

mutation of the TGFB3 latency-associated

peptide domain in a patient with

overgrowth and Loeys–Dietz syndrome

features.”

Am J Med Genet Part A 164A:2144–2145.

�Correspondence to:

Hugh Young Rienhoff, Jr., San Francisco, CA.

E-mail: hrienhoff@datahooks.com

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 9 May 2014

DOI 10.1002/ajmg.a.36603

TO THE EDITOR:

The correspondence from Matyas et al. [2014] is intriguing. The

authors have identified a mutation [c.899G>A, p.Arg300Gln] in

the portion of the TGFB3 gene coding for the cleavage recognition

site between TGFB3 propeptide or latency-associate peptide (LAP)

and the mature TGFB3 ligand. This mutation alters the second

arginine in the highly conserved cleavage site, RKKR. Though

the authors do not provide evidence, in this instance, the LAP

likely envelops the ligand normally, but free ligand cannot be

liberated; hence, predicted production of mature ligand would

be reduced by 50% and the mutation could be considered hypo-

morphic, though expressivity and penetrance might vary as a

function of differing proteases among diverse tissues. The

mutation was presumably identified by candidate gene analysis

that included several of the more commonly interrogated genes

mutated in patients with Marfanoid features. Though their

genetic analysis does not capture all the variation in the exome,

it is entirely believable that the phenotype is largely owing to the

TGFB3 mutation.

The authors make the point that this patient shared many

clinical features with the first case report of a TGFB3 coding

mutation [Rienhoff et al., 2013] but was also phenotypically

distinct in some potentially clinically significant ways: the

Maytas et al. patient showed skeletal overgrowth, her musculature

was essentially normal, and all joints were hyperextensible with

no evidence of contracture. The aortic root dimensions were

toward the upper limit of normal, which must be taken at

face value: there was no evidence of vascular disease. Could these

differences simply be attributed to different TGFB3 concentrations

with this new mutation reducing TGFB3 levels by a lesser degree

than the dominant negative TGFB3mutation reported by Rienhoff

et al. [2013]?

The Maytas et al. case is provocative because it begs a question

beyond the scope of their report: Why are there similar clinical

findings among these various allied syndromes—Camurati

Engelman, Marfan, Loeys–Dietz, Beals-Hecht—when some

mutations are thought to be hypermorphic and others hypo-

morphic? Is it possible that the newly reported mutation, as well

2014 Wiley Periodicals, Inc.

as the many other mutations affecting proteins in the TGFB

pathway, have both effects in a body, spatially distinct and

determined at the level of each affected tissue? There are many

examples in developmental biology of TGFB signaling having

opposite effects depending on, for example, intracellular signal-

ing pathways, competing ligands, local processing proteases, or

extracellular matrix compositions.

This case coupled with the previous TGFB3 report [Rienhoff

et al., 2013] suggests that loss-of-function mutations reducing

activity or production of TGFB3 ligand do not adversely affect the

cardiovascular system at a young age, unlike Loeys–Dietz syn-

drome. But TGFB3 mutations also have clinically distinct effects

for reasons unknown. That is a call to action among those who

study TGFB. The point of reporting these individual cases is to

present the conundrums these mutations pose—there is not a

comprehensive molecular understanding of TGFB biology ac-

counting for the contradictory phenotype–genotype correlations.

The Maytas et al. case represents a wonderful example of how

human mutations can show us what we don’t know, when we

thought we did.

2144

RIENHOFF 2145

REFERENCES

Matyas G, Naef P, Oexle K. 2014. De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowthand features of Loeys–Dietz syndrome. Am J Med Genet Part A(in press).

RienhoffHY, YeoC-Y,Morissette R, Khrebtukova I,Melnick J, Luo S, LengN, Kim Y-J, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG,WhitmanM. 2013. A mutation in TGFB3 associated with a syndrome oflow muscle mass, growth retardation, distal arthrogryposis, and clinicalfeatures overlapping withMarfan and Loeys–Dietz syndrome. Am JMedGenet Part A 161A:2040–2046.